Certain pyrano [3,4-b]indoles and thiopyrano[3,4-b]indoles

ABSTRACT

Indole derivatives characterized by having a 1,3,4,9-tetrahydropyrano[3,4-b]indole or 1,3,4,9-tetrahydrothiopyrano[3,4-b]indole nucleus bearing a substituent in position 1, said substituent incorporating an acid, ester or amide function therein, are disclosed. The nucleus is further substituted at position 1 and may be optionally substituted at positions 3, 4, 5, 6, 7, 8, and 9. The derivatives are useful antiinflammatory, analgesic, antibacterial and antifungal agents and methods for their preparation and use are also disclosed.

This application is a Continuation-in-Part of our earlier-filed application Ser. No. 148,895 filed June 1, 1971, now U.S. Pat. No. 3,843,681, issued Oct. 22, 1974.

BACKGROUND OF THE INVENTION

This invention relates to novel indole derivatives, to processes for their preparation and to intermediates used in these processes.

Notwithstanding the advances made during the last four decades in the development of agents for the treatment of inflammatory conditions, there still remains a need for effective agents without the side effects associated with the therapeutic agents presently used for this purpose.

The indole derivatives of this invention have been found to exhibit interesting and useful pharmacodynamic properties without eliciting undesirable side effects. Notable attributes of this effect are antinflammatory and analgesic activities. In addition the compounds of this invention exhibit antibacterial and antifungal properties.

SUMMARY OF THE INVENTION

The indole derivatives of this invention are characterized by having a pyrano[3,4-b]indole or thiopyrano[3,4-b]indole nucleus bearing a substituent at position 1, said substituent incorporating an acid, ester or amide function therein. These derivatives may be represented by formula I ##SPC1##

in which R¹ is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, phenyl, benzyl and 2-thienyl, R², R³, R⁴ and R⁵ are the same or different and are each selected from the group consisting of hydrogen and lower alkyl, R⁶ is selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro and halo, R⁷ is selected from the group consisting of hydrogen, lower alkyl and lower alkenyl, X is selected from the group consisting of oxy and thio, Y is selected from the group consisting of carbonyl, ##EQU1## which each of R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ is hydrogen or lower alkyl, and Z is selected from the group consisting of hydroxy, lower alkoxy, amino, lower alkylamino, di(lower)alkylamino and phenylamino.

Also included within the scope of this invention are pyrano[3,4-b]indole and thiopyrano[3,4-b]indole derivatives of formula I in which R⁶ represents from one to four substituents, which may be present simultaneously, at positions 5,6,7 and 8 thereof. The exact nature of such substituents does not have to be limited necessarily by the above definitions of R⁶, and R⁶ may also include additional definitions, for example, mercapto, lower alkylthio, trifluoromethyl and other halo(lower)alkyls, amino and sulfamoyl, provided that any two such substituents do not interfere with each others presence. Accordingly the indole derivatives of this invention are represented also by general formula Ia ##SPC2##

in which R¹, R², R³, R⁴, R⁵, R⁷, X, Y and Z are as defined in the first instance and R^(6a), R^(6b), R^(6c) and R^(6d) are the same or different and each is selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro, halo, mercapto, lower alkylthio, trifluoromethyl, amino and sulfamoyl.

The indole derivatives of this invention of formula I are prepared by reacting a compound of the formula ##EQU2## in which R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined in the first instance and X' is hydroxy or mercapto with a compound of formula ##EQU3## in which R¹, Y and Z are as defined in the first instance, in the presence of an acid catalyst.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-methylpentyl and the like.

The term "lower alkenyl" as used herein contemplates both straight and branched chain alkenyl radicals containing from two to six carbon atoms and includes vinyl, allyl, 1-propenyl, methallyl, 2-ethyl-3-butenyl and the like.

The term "lower alkynyl" as used herein contemplates both straight and branched chain alkynyl radicals containing from two to six carbon atoms and includes ethynyl, propargyl, 1,1-dimethylpropargyl and the like.

The term "lower cycloalkyl" as used herein contemplates saturated cyclic hydrocarbon radicals containing from three to six carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl and the like.

The term "lower alkoxy" as used herein contemplates both straight and branched chain alkoxy radicals containing from one to four carbon atoms and includes methoxy, ethoxy, isopropoxy and the like.

The term "lower alkanoyloxy" as used herein contemplates both straight and branched chain alkanoyloxy radicals containing from two to six carbon atoms and includes acetoxy, propionyloxy, hexanoyloxy and the like.

The term "halo" as used herein contemplates halogens and includes fluorine, chlorine, bromine and iodine.

Where the term "lower" is used herein as part of the description of alkylamino and dialkylamino, it contemplates one to six carbon atoms for each alkyl group of such a radical and includes methylamino, n-hexylamino, dimethylamino, diethylamino and the like.

The indole derivatives of formula I in which Z is hydroxy, the acid compounds of this invention, form addition salts with suitable inorganic and organic bases. These salts possess the same activities as the parent acid compound when administered to animals and may be utilized in the same manner. Suitable bases to form these salts include, for example, the hydroxides, lower alkoxides, carbonates and bicarbonates of sodium, potassium, calcium and magnesium, as well as the bases, ammonia, triethylamine, benzylamine and the like. The addition salts thus obtained are the functional equivalents of the parent acid compound in respect to their therapeutic use. Hence, these addition salts are included within the scope of this invention and are limited only by the requirement that the bases employed in forming the salts be pharmaceutically acceptable.

Also included within the scope of this invention are the isomers of the compounds of formula I resulting from the asymmetric centers contained therein.

ANTIINFLAMMATORY AND ANALGESIC ACTIVITY

The useful antiinflammatory and analgesic activities of the indole derivatives of this invention may be domonstrated in standard pharmacologic tests, for example, the tests described by R.A. Turner in "Screening Methods in Pharmacology", Academic Press, New York and London, 1965, pp. 152-163 and pp. 100-117, respectively.

More particularly, the antiinflammatory activity of the compounds of this invention may be readily demonstrated in a modification of the Freund's adjuvant test, the adjuvant induced actue edema test as described by J. R. Boissier et al., Therapie, 25, 43 (1970). This test is known to correlate well with data derived from clinical results with humans. Boissier et al. have demonstrated this correlation with such clinically active compounds as phenylbutazone, mefenamic acid, indomethacin, aspirin, hydrocortisone and prednisolone.

More particularly exemplified, a substantial antinnflammatory effect for the compounds listed below in domonstrable at oral doses of 100 mg/kg or less in this actue edema test. In this test male rats are treated with the test compound one hour before the injection of Freund's adjuvant into the paw (day O). The rats are then treated with the same dose of the test compound for the next three days. The antiinflammatory effect of the test compound is measured by the reduction of pedal inflammation, see Turner cited above, and expressed as a percent inhibition from adjuvant injected control rats on day 3.

    __________________________________________________________________________                             DAILY                                                                          DOSE  PERCENT                                                     COMPOUND     (MG/KG)                                                                              INHIBITION                                       __________________________________________________________________________     1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                      indole-1-acetic acid, Example No. 1                                                                    100   30                                               1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                       indole-1-acetic acid, Example No. 15                                                                   100   47                                               1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                      indole-1-acetic acid, Example No. 16                                                                   100   40                                               8-methyl-1-propyl-1,3,4,9-tetrahydropyrano-                                    [3,4-b]indole-1-acetic acid, Example No. 26                                                            100   44                                               1-butyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                       indole-1-acetic acid, Example No. 25                                                                   100   40                                               1-t-butyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                     indole-1-acetic acid, Example No. 24                                                                   100   30                                               5-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]-                             indole-1-acetic acid, Example 32                                                                       100   44                                               1-ethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-                             1-acetic acid, Example No. 98                                                                           25   32                                               __________________________________________________________________________

The lack of side effects for the compounds of this invention may be demonstrated by standard acute toxicity tests (see Turner cited above) and by prolonged administration of the compound to warm-blooded animals.

When the present indole derivatives of this invention are employed as antiinflammatory and analgetic agents in warm-blooded animals, e.g., rats, they may be administered orally, alone or in dosage forms, i.e., capsules or tablets, combined with pharmacologically acceptable excipients, such as starch, milk sugar and so forth. They may also be administered orally in the form of solutions in suitable vehicles such as vegetable oils.

The dosage of the indole derivatives of this invention will vary with the particular compound chosen and form of administration. Furthermore, it will vary with the particular host under treatment. Generally, the compounds of this invention are administered at a concentration level that affords protective effects without any deleterious side effects. These antiinflammatorilyanalgesically effective concentration levels are usually obtained within a therapeutic range of 1.0 mg to 500 mg/kg per day, with a preferred range of 10 to 100 mg/kg per day.

Antibacterial and Antifungal Activity

The indole derivatives of this invention also exhibit utility as antibacterial agents against a number of gram-positive and gram-negative microorganisms, such as, Staphylococcus pyogenes, both penicillin sensitive and penicillin resistant, Streptococcus faecalis, Escherichia coli, Aerobacter aerogenes, Salmonella pullorum, Pseudomonas aerugenosa, Proteus mirabilis, Protues vulgaris, Klebsiella pneumoniae and Seratia marcescens and as antifungal agents against a number of pathogenic fungi such as, Candida albicans, Microsporum gypseum and Trichophyton granulosum, in standard tests for antibacterial and antifungal activity, such as those described in 37 Antiseptics, Disinfectants, Fungicides and Sterilization", G.F. Reddish, Ed., 2nd ed., Lea and Febiger, Philadelphia, 1957 or by D. C. Grove and W.A. Randall in "Assay Methods of Antibiotics", Med. Encycl. Inc., New York 1955.

For example, by employing a test like the serial broth dilution, see Grove and Randall, cited above, in which dilutions of the compounds of this invention in nutrient broth are inoculated with the microorganisms or fungi, described above, incubated at 37°C. for 2 days, respectively, and examined for the presence of growth, it may be shown that 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid is able to inhibit growth totally in this system of Proteus vulgaris, Klebsiella pneumoniae and Serratia marcescens at a concentration of 100 mcg/ml. or less.

When the compounds of this invention are employed as antibiotic or antifungal agents in warm-blooded animals, e.g. rats, they may be administered alone or in combination with pharmacologically acceptable carriers. The proportion of the compound is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice. For example, they may be administered orally in solid form containing such excipients as starch, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents as antibiotic or antifungal agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford antibacterially or antifungally effective results without causing any harmful or deleterious side effects and preferably at a level that is in a range of from about 1.0 mg. to about 1000 mg. per kilo per day, although as aforementioned variations will occur. However, a dosage level that is in the range of from about 10 mg. to about 500 mg. per kilo per day is most desirably employed in order to achieve effective results.

In addition, the agent may be employed topically. For topical application they may be formulated in the form of solutions, creams, or lotions in pharmaceutically acceptable vehicles containing 0.1-5 per cent, preferably 2 per cent, of the agent and may be administered topically to the infected area of the skin.

Also the antibacterial properties of the compounds of this invention may be utilized for washing equipment in hospitals, homes and farms, instruments used in medicine and bacteriology, clothing used in bacteriological laboratories, and floors, walls and ceiling in rooms in which a background free of gram-positive and gram-negative microorganisms, such as those listed above, is desired. When employed in this manner the compounds of this invention may be formulated in a number of compositions comprising the active compound and an inert material. In such compositions, while the compounds of formula I of this invention may be employed in concentrations as low as 500 p.p.m., from a practical point of view, it is desirable to use from about 0.10% by weight, to about 5% by weight or more.

The formulations that may be used to prepare antiseptic wash solutions of the compounds of this invention are varied and may readily be accomplished by standard techniques, see for example, "Remington's Practice of Pharmacy", E.W. Martin et al., Eds., 12th ed., Mack Publishing Company, Easton, Penn., 1961, pp. 1121 - 1150. In general, the compounds may be made up in stock solutions. They can also be formulated as suspensions in an aqueous vehicle. These make useful mixtures for decontaminating premises. Also, aqueous vehicles containing emulsifying agents, such as sodium lauryl sulfate, and relatively high concentrations, e.g., up to about 5% by weight, of the compounds may be formulated by conventional techniques.

A typical antiseptic preparation useful for disinfecting floors, walls, ceiling, and articles in a contaminated room may be prepared by adding 5 to 25 g. of N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide to a mixture of 150 to 300 g. of polyethylene glycol 1540 and 150 to 300 g. of polyethylene glyol 300. The resulting mixture is stirred while a solution of 1 to 10 g. of sodium lauryl sulfate in 300 to 400 ml. of water is added portionwise. The article to be disinfected is coated or immersed in the preparation for a prolonged time, for example, one hour, and then rinsed with sterile water.

Preparation of Indole Derivatives

For the preparation of the indole derivatives of this invention we prefer to use as starting materials the compounds of the general formula II.

in which R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined in the first instance and X' is hydroxy or mercapto.

The starting materials of formula II in which X' is hydroxy are either known, for example, tryptophol, described by H. R. Synder and F. J. Pilgrim, J. Am. Chem. Soc. 70, 3770 (1948), or they may be obtained by the following process: ##EQU4##

With reference to this process phenylhydrazines of formula III and the hydroxyaldehyde of formula IV are reacted together according to the conditions of the "Fischer Indole Synthesis", for example, see P.L. Julian, E. N. Myer and H.C. Printy, "Heterocyclic Compounds", R.C. Elderfield, Ed., Vol. 3, John Wiley and Sons, Inc., New York, 1952, pp. 8 - 11, to form the desired starting material (II, X' = OH).

The phenylhydrazines of formula III are either known or may be prepared according to known methods. A convenient method involves the diazotization of the appropriately substituted aniline to give the corresponding diazo derivative. The latter compound is then reduced with stannous chloride or sodium sulfite to give the corresponding phenylhydrazine, see L. F. Fieser and M. Fieser, "Advanced Organic Chemistry", Reinhold Publishing Corporation, New York, 1961, p. 734.

The hydroxyaldehydes of formula IV are either known, see for example, "Rodd's Chemistry of Carbon Compounds," S. Coffey, Ed., Vol. I d, 2nd ed., Elsevier Publishing Co., Amsterdam, 1965, pp. 44 - 49, or they may be prepared according to known methods. A convenient method involves reduction of an appropriate lactone of formula O=C-CH₂ C(R⁴)(R⁵)C(R²)(R³)-O with bis-(3-methyl-2-butyl)borane, H. C. Brown and D. B. Bigley, J. Am. Chem. Soc., 83, 486 (1961), diisobutyl aluminum hydride, L. I. Zakharkkin and I. M. Khorlina, Tetrahedron Letters, 619 (1962) or sodium aluminum hydride, L. I. Zakharkin et al., Tetrahedron Letters, 2087 (1963). The appropriate lactones utilized in this condensation are either commercially available, for example, δ-valerolactone, α-methyl-butyrolactone, or they are described with a variety of methods for their preparation in organic chemistry textbooks; such as the textbooks, "Methoden der Organischen Chemie", Houben-Weyl, E. Muller, Ed., Vol. VI/2, Georg Thieme Verlag, Stuttgart, 1963, pp. 561 - 852 or L. F. Fieser and M. Fieser, "Advanced Organic Chemistry", cited above.

Alternatively, the starting materials of formula II in which R², R³, R⁴ and R⁷ are hydrogen and X' is hydroxy may be prepared by lithium aluminum hydride reduction, N. G. Gaylord, "Reduction with Complex Metal Hydrides", Interscience Publishers, Inc., New York, 1956, pp. 322 - 370, of compounds of formula V described by T. Y. Shen, U.S. Pat. No. 3,161,654, Dec. 15, 1964: ##SPC3##

wherein R¹⁵ is lower alkyl and R⁵ and R⁶ are as defined in the first instance.

The starting materials of formula II in which X' is mercapto and R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined in the first instance may be obtained by the following process: The appropriate compound of formula II (X' = OH), described above, is treated with phosphorus tribromide in an inert solvent, for example, ether or carbon tetrachloride, to afford the corresponding 3-(2-bromoethyl)indole derivative. The latter compound is then converted to the desired starting material of formula II (X' = SH) by a procedure similar to that described by N.N. Suvorov and V. N. Buyanov, Khim.-Farm. Zh., 1, 4 (1967), [Chem. Abstr. 67, 73474_(a) (1967)], for converting 3-(2-bromethyl)indole to indole-3-ethanethiol (II; R², R³, R⁴, R⁵, R⁶ and R⁷ = H and X' = SH). Accordingly, the appropriate 3-(2-bromethyl)indole derivative is treated with sodium or potassium thiosulfate to afford the corresponding sodium or potassium β-(3-indolyl)ethyl thiosulfate derivative, respectively, which on treatment with strong alkali for example, sodium or potassium hydroxide, is transformed into the corresponding bis-[ω-(3-indolyl)ethyl]disulfide derivative. Reduction of the latter compound with lithium aluminum hydride gives the desired compounds of formula II.

It should be noted that the preceding process is not entirely practical for the preparation of the compounds of formula II in which X' is mercapto and R⁶ is hydroxy or lower alkanoyloxy. For this reason, the preferred starting materials of formula II for the ultimate preparation of the compounds of formula I in which R⁶ is hydroxy or lower alkanoyloxy and X is thio are the corresponding compounds of formula II in which R⁶ is benzyloxy, readily prepared by this process. When the latter compounds are used as starting materials in this manner, they are first subjected to the process (II + VI →VII), described below. Subsequently, the benzyloxy group is removed by hydrogenation, in the presence of a catalyst, for example, 10% palladium on carbon, to afford the corresponding compound of formula I in which R⁶ is hydroxy. The latter may be converted if desired to the corresponding compound of formula I in which R⁶ is lower alkanoyloxy by conventional means, for example, by treatment with the appropriate lower alkanoic anhydride preferably in the presence of pyridine. Likewise, it should be noted that similar use of the starting materials of formula II in which X' is hydroxy and R⁶ is benzyloxy to obtain the corresponding compound of formula I in which R⁶ is hydroxy or lower alkanoyloxy is preferred.

For the preparation of the acid and ester compounds of this invention of formula I in which Z is hydroxy or lower alkoxy and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Y are as defined in the first instance, we have found that the following, hitherto undisclosed process is both practical and convenient: ##EQU5## in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, Y, and Z are as defined in this instance, X' is hydroxy or mercapto and R¹⁶ is hydrogen or lower alkyl. (For convenience and clarity these particular acid and ester compounds of formula I are represented above as formula VII).

With reference to the above scheme the starting material of formula II is condensed with a ketoacid (VI, R¹⁶ = H) or a ketoester (VI, R¹⁶ = lower alkyl) in the presence of a suitable acid catalyst to yield the compounds of formula VII.

Generally comparable yields of product are obtained in this process when either the ketoacid or the corresponding ketoester is used. However, in the case where it is desired to prepare acid compounds of formula VII in which Y is ##EQU6## and R¹⁶ is hydrogen, it is preferable with respect to yield to first condense the appropriate β-ketoester of formula VI rather than the corresponding β-ketoacid and then hydrolyze the resulting ester product to give the desired acid compound.

Moreover, in the general practise of this invention it is often more convenient to prepare the acid compounds of formula VII by using the ketoester instead of the ketoacid in this process and then hydrolyze the resulting ester product to the desired acid, the reason being simply that the ketoesters are generally more readily available either commercially or by synthesis.

The hydrolysis of compounds of formula VII in which R¹⁶ is lower alkyl to their corresponding acids of formula VII is readily effected by treatment with a suitable alkali, for example, potassium hydroxide or sodium carbonate, in aqueous methanol or aqueous ethanol.

In practising the condensation (II + VI → VII) we have found it preferable to use a solvent as a reaction medium. Any solvent inert to the reaction conditions may be used. Suitable solvents include benzene, toluene, diethyl ether, dioxan, tetrahydrofuran, methylene dichloride, carbon tetrachloride and the like. Benzene and tetrahydrofuran are especially convenient and practical for this use. A variety of suitable acid catalysts may be used for this condensation, for example, the type of catalyst used in a Fischer Indole Synthesis, i.e. p-toluenesulfonic acid, phosphorus pentoxide, boron trifluoride, zinc chloride, hydrochloric acid and sulfuric acid and the like. p-Toluenesulfonic acid, boron trifluoride and phosphorus pentoxide are included among the preferred acid catalysts. The amount of acid catalyst used is not especially critical and may range from 0.01 molar equivalents to 100 molar equivalents; however, a range of from 0.1 to 10 molar equivalents is generally preferred. The time of the reaction may range from 10 minutes to 60 hours, with the preferred range being from one-half to 24 hours. The temperature of the reaction may range from -20° C. to the boiling point of the reaction mixture. Preferred temperature ranges include 20° to 120°C.

The α-, β-, γ- and δ- ketoacids and -ketoesters of formula VI are either known, for example, ethyl pyruvate, levulinic acid, ethyl α, α-dimethylacetoacetate, β, β-dimethyllevulic acid and benzoylacetic acid or they may be prepared by known methods described in general organic chemistry textbooks. For example, a comprehensive review on the properties and preparation of such α-, β-, γ- and δ- ketoacids and -ketoesters may be found in "Rodd's Chemistry of the Carbon Compounds", cited above, Vol, 1d, pp. 226 - 274.

Alternatively, the acid compounds of formula I in which Z is hydroxy and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and y are as defined in the first instance may be prepared by the following process: ##SPC4## in which Y' is CH₂, C(R⁸)(R⁹)CH₂, C(R⁸)(R⁹)C(R¹⁰) (R¹¹)CH₂ or C(R⁸)R⁹)C(R¹⁰)(R¹¹)C(R¹²)(R¹³)CH₂, R¹⁷ is hydrogen or lower alkyl, Z is hydroxy and R¹, R², R³, R⁴ , R⁵ , R⁶, R⁷, X and Y are as defined in the first instance.

With reference to this alternative process a starting material of formula II is condensed with a ketoalcohol lower alkyl ester (VIII) in the presence of a suitable acid catalyst according to the conditions described above for the condensation (II + VI→VII). The ketoalcohol lower alkyl esters are either known, for example, acetonyl acetate or 5-acetoxypentan-2-one, or may be prepared by known methods, for instance, see "Rodd's Chemistry of the Carbon Compounds", cited above, Vol. ld, pp. 49 - 54. In this manner the condensation product of general formula IX is obtained. Hydrolysis of this product with an aqueous alcoholic solution of a suitable alkali, for example, sodium hydroxide in aqueous methanol, affords the corresponding primary alcohol X. The primary alcohol is then oxidized to the corresponding aldehyde of formula XI. Although a variety of methods are known for the oxidation of a primary alcohol to its corresponding aldehyde, see for example, "Rodd's Chemistry of the Carbon Compounds", cited above, Vol.. 1c, pp. 4 - 10, we have found that the method of K. E. Pfitzner and J. G. Moffat, J. Am. Chem. Soc., 87, 5670 (1965) using N,N-dicyclohexylcarbodiimide and dimethyl sulfoxide in the presence of a suitable acid, for example, trifluoroacetic acid, to be both efficacious and convenient in this case, Subsequently the aldehyde XI may be converted to the desired acid compounds of formula I by a variety of oxidizing agents, including silver oxide, alkaline permanganate, hydrogen peroxide, peracids and the like. In this case we prefer to use silver oxide according to the method of M. Delepine and P. Bonnet. Compt. rend., 149,39 (1909).

The amide compound of this invention of formula I in which Z is amino, lower alkylamino, di(lower)alkylamino and phenylamino and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Y are as defined in the first instance, may be prepared from their corresponding acid compounds of formula I (compounds of formula VII in which R¹⁶ is hydrogen, described above) by treatment of the latter compounds with a lower alkyl chloroformate, preferably ethyl chloroformate, in the presence of triethylamine, affording the corresponding mixed anhydride, which is converted by treatment with the appropriate amine, such as ammonia, aniline or a suitable alkylamine or dialkylamine, to the desired amide compound of formula I.

Alternatively, these amides of formula I may be prepared from the corresponding esters of formula I (compounds of formulae VII, in which R¹⁶ is lower alkyl, described above) by treatment of the latter compounds with the appropriate amine according to known methods, for example, see A. L. J. Beckwith in "The Chemistry of Amides", J. Zalicky, Ed., Interscience Publishers, New York, 1970, pp. 96 - 105.

Again alternatively, the amide compounds of formula I in which Z is amino, lower alkylamino, di(lower)alkylamino, and phenylamino and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Y are as defined in the first instance, may be prepared by the condensation of an apapropriate starting material of formula II with an appropriate α-, β-, γ- or δ-ketoamide in the presence of a suitable acid catalyst according to the conditions described above for the condensation (II + VI → VII). The ketoamides required for this condensation are either known, for example, pyruvamide or α,α-dimethylacetoacetamide, or they may be prepared by known methods, for instance, see "Rodd's Chemistry of the Carbon Compounds", cited above, Vol. 1d, pp. 226 - 274.

The alkylated acid and ester compounds of this invention of formula I in which R⁷ is lower alkyl or lower alkenyl and Z is hydroxy or lower alkoxy, are prepared readily from the above described, corresponding acid or ester compounds of formula I in which R⁷ is hydrogen. This conversion involving the N-alkylation of the indolic nitrogen is effected by treatment of the latter compounds with an appropriate lower alkyl or lower alkenyl halide in an inert solvent in the presence of an acid acceptor. Preferred conditions for effecting this conversion include the use of sodium hydride as an acid acceptor and tetrahydrofuran as the inert solvent.

The N-alkylated amide compounds of formula I in which R⁷ is lower alkyl or lower alkenyl and Z is amino, lower alkylamino, di(lower)alkylamino or phenylamino are preferably prepared by either treatment of the N-alkylated acid compounds of formula I, described above, with a lower alkyl chloroformate followed by treatment with the appropriate amine, or treatment of the N-alkylated ester compounds of formula I, described above, with an appropriate amine, in the manner described previously for the preparation of the amide compounds of formula I in which R⁷ is hydrogen.

Finally, it is the intention to cover all changes and modifications of the embodiment of the invention herein chosen for the purpose of disclosure which are within the scope and spirit of this invention. Such changes and modification include those variations which depend on well known interconversions of acids and esters or alternation of the order of N-alkylation in the processes disclosed herein.

For example, in preparing the N-alkylated acid, ester or amide compounds of formula I in which R⁷ is lower alkyl or lower alkenyl, the changing of the order of the N-alkylation step, as depicted in the embodiment of this invention, by the act of N-alkylation of the starting materials of formula II and subjecting the products thereof to treatment with an appropriate ketoacid or ketoester of formula VI or a ketoamide, according to the teaching of the present disclosure, would not depart from the spirit or scope of this invention.

Likewise, the preparation of the N-alkylated amide compounds of formula I in which R⁷ is lower alkyl or lower alkenyl and Z is di(lower)alkylamino by N-alkylation of the corresponding compounds of formula I in which R⁷ is hydrogen, is considered to be a process which would be functionally equivalent to the process embodied herein for the preparation of these compounds.

It will also be apparent to those skilled in the art that the processes taught herein for the preparation of the indole derivatives of formula I are applicable likewise to the preparation of the indole derivatives of formula Ia, described above. In the latter case, the appropriate starting material of formula IIa, see below, prepared analogously to the starting material of formula II, is utilized.

More specifically, the acid and ester compounds of formula Ia in which R^(6a), R^(6b), R^(6c), R^(6d) and R⁷ are as defined in the first instance, Z is hydroxy or lower alkoxy, and R¹,R², R³, R⁴, R⁵ , X and Y are as defined in the first instance, are readily prepared by the condensation (IIa+VI→ VIIa), illustrated below, according to the conditions described previously for the condensation (II+VI→VII). ##SPC5##

in which R¹, R², R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c), R^(6d), R⁷, X, Y and R¹⁶ are as defined in the first instance.

Likewise, the acid compounds of formula Ia in which R^(6a), R^(6b), R^(6c) , R^(6d) are as defined in the first instance, Z is hydroxy and R¹, R², R³, R⁴ , R⁵, R⁷ , X and Y are as defined in the first instance may be prepared by the following process: ##SPC6##

in which R¹, R², R³,R⁴ , R⁵ , X, Y, Y', R^(6a), R^(6b), R^(6c), R^(6d), R⁷, and R¹⁷ are as defined in the first instance according to the process disclosed above for the conversion [II+VIII →IX →X→XI→I (Z= OH)]. Subsequent transformation of the above acid and ester compounds of formula Ia to their corresponding N-alkylated and amide derivatives of formula Ia is effected in the same manner for the similar conversions of the acid ester compounds of formula I, described herein.

Alternatively, the amide derivatives of formula Ia are prepared by the condensation of an appropriate starting material of formula IIa with an appropriate α-, β-, γ- or δ-ketoamide in the presence of a suitable acid catalyst according to the conditions described previously for the condensation (II + VI → VII).

The following examples will illustrate further this invention.

EXAMPLE 1 1METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-ACETIC ACID (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X, = O, Y, = CH₂ CO AND Z = OH)

Ethyl acetoacetate (23.4 g., 0.18 moles) is added to a solution of the starting material of formula II, tryptophol (10.0 g., 0.06 moles), in 200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonic acid (1.3 g.) and about 5 g. of hydrated alkali-aluminum silicate (Molecular Sieves No. 4) are added. The mixture is subjected to reflux for 30 minutes, 600 mg. more of p-toluenesulfonic acid is added and refluxing continued for 21/2hours. The molecular sieves are collected and the benzene solution washed successively with 5% sodium bicarbonate and water, dried over sodium sulfate, and evaporated under reduced pressure to dryness affording an oil. The oil is subjected to chromatography on silica gel. Elution with 5% ether in benzene yields the ester, 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid ethyl ester, as an oil,.sbsp.3_(max) ^(CHCl) 3 1715 cm.sup.⁻¹ .

Hydrolysis of this ester to the title compound is effected as follows: The ester is dissolved in 230 ml. of methanol. To this is added 10 g. of KOH in 30 ml. of H₂ O and the solution is allowed to stand at room temperature overnight. The methanol is evaporated, water added and the solution washed with benzene. The aqueous phase is acidified with 6N HCl, and extracted with benzene. This organic phase is washed with water, dried over sodium sulfate and evaporated to dryness to give an oil, which is crystallized from benzene containing a trace of petroleum ether to afford the title compound, m.p. 150°- 152°C., .sbsp.3_(max) ^(CHCl) 3 3325 and 1705 cm.sup.⁻¹ .

An equivalent amount of methyl acetoacetate may replace ethyl acetoacetate in the procedure of this Example. In this case, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-acetic acid methyl ester, m.p. 87° -90°C. after recrystallization from benzenehexane, is obtained as the ester.

An equivalent amount of propyl acetoacetate may replace ethyl acetoacetate in the procedure of this Example. In this case, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid propyl ester is obtained as the ester.

EXAMPLE 2 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-PROPIONIC ACID (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O, Y = CH₂ CH₂ CO AND Z = OH)

A mixture of the starting material of formula II, tryptophol (500 mg.), levulinic acid (580 mg.), 75 ml. of benzene, 1.7 g. of phosphorus pentoxide and about 0.5 g. of diatomaceous earth (Celite) is stirred magnetically at room temperature for 15 minutes and then at 70°C. for 11/2 hr. The reaction mixture is filtered. The filtrate is washed three times with 5N NaOH; the combined aqueous phase is washed twice with ether and then rendered acidic with cold 50% HCl. The aqueous phase is extracted with chloroform. The chloroform extract is dried (Na₂ SO₄) and evaporated to dryness. The residue is crystallized from ethyl acetate-petroleum ether to afford the title compound, m.p. 104° -110°C., nmr (CDCl₃) δ 1.47 (3H), 2.18 (4H), 2.74 (2H), 3.96 (2H), 7.18 (4H), 7.85 (1H), 9.60 (1.H).

The above title compound is also obtained by following the procedure of Example 1 but replacing ethyl acetoacetate with an equivalent amount of ethyl levulinate. In this case 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid ethyl ester, m.p. 116°-118°C., ν_(max) ^(CHCl) .sbsp.3 1716 cm.sup.⁻¹, after crystallization from benzene-petroleum ether, is obtained as the ester prior to hydrolysis.

EXAMPLE 3 1-METHYL-1,3,4,9-TETRAHYDROTHIOPYRANO[3,4-b]INDOLE-1-ACETIC ACID (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = S, Y = CH₂ CO AND Z = OH)

Indole-3-ethanethiol (1.5 g.) and methyl acetoacetate are mixed with 50 ml. of benzene and the solution heated for 30 min. (bath temperature 70° - 80°C.). p-Toluenesulfonic acid (0.15 g.) is added and the reaction mixture is subjected to reflux and stirring for 12 hours. Water formed in the reaction mixture during this period is collected by a water separator. After cooling the benzene solution is washed with a 10% solution of sodium bicarbonate, water, saturated brine and dried over sodium sulfate. Evaporation of the benzene solution yields the ester, 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester as a semi-solid, νν_(CHCl) .sbsp.3 1715 cm.sup.⁻¹.

This ester is then treated with aqueous alcoholic KOH in the manner described for the esters in Example 1 and 2 to afford the title compound, m.p. 147° - 149°C., nmr (CDCl₃) δ1.86 (S, 3H), 3.06 and 8.12 (6H), 7.35 (multiplet, 4H), 8.71 (1H), 10.31 (1H), after recrystallization from benzene-hexane.

The procedures of Examples 1, or 3 may be followed to prepare other compounds of formula I in which R¹, R², R³, Rhu 4, R⁵, R⁶, X and Y are as defined in the first instance, R⁷ is hydrogen and Z is hydroxy. Examples of such compounds of formula I are listed Tables I and II. In each of these examples an equivalent amount of the starting material of formula II listed therein is used instead of the starting material of formula II described in the procedures of Examples 1 and 3. Note that in each of these examples the ester obtained prior to hydrolysis is the corresponding ester compound of formula I in which Z is a lower alkoxy of the product listed therein, the alkyl portion of said lower alkoxy being derived from the R¹⁶ portion of the ketoester of formula VI employed therein.

Similarly, the procedure of Example 2 may be used to prepare the products listed in Tables I and II. In this case an equivalent amount of the starting material of formula II, listed therein is used instead of the starting material of formula II described in Example 2 and an equivalent amount of the corresponding ketoacid of formula VI of the ketoester of formula VI listed therein is used instead of the said ketoester.

                                      TABLE I                                      __________________________________________________________________________                                                 KETOESTER OF                                                                   FORMULA VI                              STARTING MATERIAL OF                   O                                                                              ∥                         EXAMPLE                                                                             FORMULA II                             (R.sup.1 --C--Y--OR.sup.16)        R.sup.2   R.sup.3                                                                           R.sup.4                                                                             R.sup.5                                                                             R.sup.6  X R.sup.1  Y                R.sup.16           __________________________________________________________________________      4   H    H  H    H    H        O CH.sub.3 CO               C.sub.2                                                                        H.sub.5             5   CH.sub.3                                                                            H  H    H    H        O C.sub.2 H.sub.5                                                                         CO               C.sub.2                                                                        H.sub.5             6   n--C.sub.3 H.sub.7                                                                  H  H    H    5--CH.sub.3                                                                             O n--C.sub.3 H.sub.7                                                                      CO               CH.sub.3            7   CH.sub.3                                                                            CH.sub.3                                                                          H    H    5--OH    O CH.sub.3 CH=CH                                                                          CO               CH.sub.3            8   H    H  H    H    7--C.sub.2 H.sub.5                                                                      O HC.tbd.C CO               CH.sub.3            9   H    H  2--C.sub.3 H.sub.7                                                                  H    H        O          CO               CH.sub.3           10   CH.sub.3                                                                            CH.sub.3                                                                          C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     H        O          CO               CH.sub.3           11   H    H  H    H    H        O          CO               CH.sub.3           12   CH.sub.3                                                                            C.sub.2 H.sub.5                                                                   H    H    H        O --CH.sub.2                                                                              CO               CH.sub.3           13   H    H  H    H    6--Cl    O          CO                                  14   H    H  CH.sub.3                                                                            H    H        O CH.sub.3 CH.sub.2 CO      C.sub.2                                                                        H.sub.5            15   H    H  H    H    H        O C.sub.2 H.sub.5                                                                         CH.sub.2 CO      C.sub.2                                                                        H.sub.5            16   H    H  H    H    H        O n--C.sub.3 H.sub.7                                                                      CH.sub.2 CO      C.sub.2                                                                        H.sub.5            __________________________________________________________________________                                                 KETOESTER OF                            STARTING MATERIAL OF                   FORMULA VI                         EXAMPLE                                                                             FORMULA II                             (R.sup.1 --CO--Y--OR.sup.16)            R.sup.2                                                                             R.sup.3                                                                           R.sup.4                                                                             R.sup.5                                                                             R.sup.6  X R.sup.1  Y                R.sup.16           __________________________________________________________________________     17   H    H  H    H    H        O i--C.sub.3 H.sub.7                                                                      CH.sub.2 CO      C.sub.2                                                                        H.sub.5            18   CH.sub.3                                                                            H  H    H    H        O CH.sub.2 =CHCH.sub.2                                                                    CH.sub.2 CO      C.sub.2                                                                        H.sub.5            19   CH.sub.3                                                                            H  H    H    H        O n--C.sub.3 H.sub.7                                                                      CH.sub.2 CO      C.sub.2                                                                        H.sub.5            20   CH.sub.3                                                                            H  C.sub.2 H.sub.5                                                                     CH.sub.3                                                                            H        O HC.tbd.C CH.sub.2 CO      C.sub.2                                                                        H.sub.5            21   H    H  H    H    H        O CH.sub.3 CH(CH).sub.3 CO  C.sub.2                                                                        H.sub.5            22   H    H  H    H    H        O          C(CH.sub.3).sub.2 CO                                                                            C.sub.2                                                                        H.sub.5            23   H    H  H    H    H        O          CH.sub.2 CO      C.sub.2                                                                        H.sub.5            24   H    H  H    H    H        O t--C.sub.4 H.sub.9                                                                      CH.sub.2 CO      C.sub.2                                                                        H.sub.5            25   H    H  H    H    H        O n--C.sub.4 H.sub.9                                                                      CH.sub.2 CO      C.sub.2                                                                        H.sub.5            26   H    H  H    H    7--CH.sub.3                                                                             O n--C.sub.3 H.sub.7                                                                      CH.sub.2 CO      C.sub.2                                                                        H.sub.5            27   H    H  H    H    H        O          CH.sub.2 CO      C.sub.2                                                                        H.sub.5            28   H    H  H    H    5--Br    O C.sub.2 H.sub.5                                                                         CH.sub.2 CO      C.sub.2                                                                        H.sub.5            29   H    H  H    H    5--OCH.sub.3                                                                            O CH.sub.3 CH.sub.2 CO      CH.sub.3           30   H    H  H    H    5--OCOCH.sub.3                                                                          O CH.sub.3 CH.sub.2 CO      C.sub.2                                                                        H.sub.5            31   H    H  H    H    5--benzyl-                                                                              O CH.sub.3 CH.sub.2 CO      C.sub.2                                                                        H.sub.5                                   oxy                                                     32   H    H  H    H    4--CH.sub.3                                                                             O n--C.sub.3 H.sub.7                                                                      CH.sub.2 CO      C.sub.2                                                                        H.sub.5            33   H    H  H    H    6--CH.sub.3                                                                             O n--C.sub.3 H.sub.7                                                                      CH.sub.2 CO      C.sub.2                                                                        H.sub.5            34   H    H  H    H    5--NO.sub.2                                                                             O n--C.sub.3 H.sub.7                                                                      CH.sub.2 CO      C.sub.2                                                                        H.sub.5            35   i--C.sub.3 H.sub.7                                                                  H  i--C.sub.3 H.sub.7                                                                  H    5--NO.sub.2                                                                             O CH.sub.2 =CH                                                                            CH(CH.sub.3)OC   C.sub.2                                                                        H.sub.5            36   H    H  CH.sub.3                                                                            CH.sub.3                                                                            H        O n--C.sub.3 H.sub.7                                                                      CH.sub.2 CO      C.sub.2                                                                        H.sub.5            37   H    H  C.sub.2 H.sub.5                                                                     H    7--CH.sub.3                                                                             O HC.tbd.C C(i--C.sub.3 H.sub.7).sub.2                                                                     C.sub.2                                                                        H.sub.5            38   CH.sub.3                                                                            CH.sub.3                                                                          H    H    5--OC.sub.2 H.sub.5                                                                     O          CH(C.sub.2 H.sub.5)CO                                                                           C.sub. 2                                                                       H.sub.5            39   CH.sub.3                                                                            CH.sub.3                                                                          C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     6--C.sub.2 H.sub.5                                                                      O          C(CH.sub.3).sub.2 CO                                                                            C.sub.2                                                                        H.sub.5            40   CH.sub.3                                                                            H  n--C.sub.3 H.sub.7                                                                  n--C.sub.3 H.sub.7                                                                  4--n--C.sub.3 H.sub.7                                                                   O          CH(CH.sub.3)CO   C.sub.2                                                                        H.sub.5            41   H    H  H    H    H        O          C(CH.sub.3).sub.2 CO                                                                            C.sub.2                                                                        H.sub.5            42   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     4--C.sub.2 H.sub.5                                                                      O --CH.sub.2 --                                                                           C(i--C.sub.3 H.sub.7).sub.2                                                                     C.sub.2                                                                        H.sub.5                                   O                                                                              ∥                                              43   CH.sub.3                                                                            H  H    H    7--OCC.sub.2 H.sub.5                                                                    O --CH.sub.2 --                                                                           C(CH.sub.3).sub.2 CO                                                                            C.sub.2                                                                        H.sub.5            44   H    H  CH.sub.3                                                                            H    H        O          CH(CH.sub.3)CO   C.sub.2                                                                        H.sub.5            45   H    H  H    H    H        O          C(CH.sub.3).sub.2 CO                                                                            C.sub.2                                                                        H.sub.5            46   H    H  H    H    4--I     O i--C.sub.3 H.sub.7                                                                      CH.sub.2 CH.sub.2 CO                                                                            C.sub.2                                                                        H.sub.5                                   O                                                                              ∥                                              47   CH.sub.3                                                                            CH.sub.3                                                                          CH.sub.3                                                                            CH.sub.3                                                                            7--OCCH.sub.3                                                                           O CH.sub.2 =CH                                                                            CH.sub.2 CH(CH.sub.3)CO                                                                         C.sub.2                                                                        H.sub.5            48   H    H  H    H    6--OH    O HC.tbd.C--CH.sub.2                                                                      CH.sub.2 C(C.sub.2 H.sub.5).sub                                                .2 CO            C.sub.2                                                                        H.sub.5            49   CH.sub.3                                                                            H  H    H    7--NO.sub.2                                                                             O          CH(n--C.sub.3 H.sub.7)CH.sub.2                                                 CO               C.sub.2                                                                        H.sub.5            50   H    H  CH.sub.3                                                                            H    5--CH.sub.3                                                                             O          C(CH.sub.3).sub.2 C(CH.sub.2)CO                                                .                C.sub.2                                                                        H.sub.5            51   i--C.sub.3 H.sub.7                                                                  H  H    H    7--Br    O --CH.sub.2                                                                              CH(CH.sub.3)CH(C.sub.2                                                         H.sub.5)CO       C.sub.2                                                                        H.sub.5            52   C.sub.2 H.sub.5                                                                     H  C.sub.2 H.sub.5                                                                     H    7--Cl    O          CH.sub.2 CH.sub.2                                                                               C.sub.2                                                                        H.sub.5            53   CH.sub.3                                                                            H  H    H    H        O CH.sub.3 CH.sub.2 C(n--C.sub.3 H.sub.7).                                                sub.2 CO         C.sub.2                                                                        H.sub.5            54   CH.sub.3                                                                            H  C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     H        O CH.sub.2 =C--CH.sub.2                                                                   CH(CH.sub.3)C(CH.sub.3).sub.2                                                  CO               CH.sub.3                                             |                                                                     CH.sub.3                                     55   H    H  CH.sub.3                                                                            CH.sub.3                                                                            H        O HC.tbd.C C(CH.sub.3).sub.2 CH.sub.2                                                                      CH.sub.3                                  O                                                                              ∥                                              56   H    H  n--C.sub.3 H.sub.7                                                                  H    4--OCC.sub.2 H.sub.5                                                                    O          C(C.sub.2 H.sub.5).sub.2                                                       C(C.sub.2 H.sub.5)CO                                                                            CH.sub.3           57   n--C.sub.3 H.sub.7                                                                  H  H    H    4--OCH.sub.3                                                                            O          CH.sub.2 CH(CH.sub.3)CO                                                                         C.sub.2                                                                        H.sub.5            58   H    H  i--C.sub.3 H.sub.7                                                                  H    6--benzyl-                                                                              O --CH.sub.2                                                                              CH.sub.2 CH(C.sub.2 H.sub.5)CO                                                                  C.sub.2                                                                        H.sub.5                                   oxy                                                     59   CH.sub.3                                                                            CH.sub.3                                                                          CH.sub.3                                                                            CH.sub.3                                                                            7--Cl    O          CH(CH.sub.3)CH.sub.2 CO                                                                         C.sub.2                                                                        H.sub.5            60   C.sub.2 H.sub.5                                                                     H  H    H    5--NO.sub.2                                                                             O CH.sub.3 CH(C.sub.2 H.sub.5).sub.2                                                      C(C.sub.2 H.sub.5).sub.2                                                                        C.sub.2                                                                        H.sub.5            61   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   H    H    5--F     O CH.sub.2 =CHCH.sub.2                                                                    CH(C.sub.2 H.sub.5)CH(CH.sub.3)                                                CO               C.sub.2                                                                        H.sub.5            62   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   H    H    4--C.sub.2 H.sub.5                                                                      O CH.sub.3 C.tbd.CH                                                                       C(n--C.sub.3 H.sub.7)CH.sub.2                                                  CO               CH.sub.3           63   H    H  H    H    6--OC.sub.2 H.sub.5                                                                     O          CH(C.sub.2 H.sub.5)CH(C.sub.2                                                  H.sub.5)CO       C.sub.2                                                                        H.sub.5            64   CH.sub.3                                                                            CH.sub.3                                                                          CH.sub.3                                                                            CH.sub.3                                                                            6--O--n--C.sub.3 H.sub.7                                                                O          C(CH.sub.3).sub.2 CH(CH.sub.3)C                                                O                C.sub.2                                                                        H.sub.5            65   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   H    H    5--CH.sub.3                                                                             O  --CH.sub.2                                                                             C(CH.sub.3).sub.2 C(CH.sub.3).s                                                ub.2 CO          C.sub.2                                                                        H.sub.5            66   n--C.sub.3 H.sub.7                                                                  H  H    H    4--OH    O          C(CH.sub.3).sub.2 C(CH.sub.3).s                                                ub.2 CO          C.sub.2                                                                        H.sub.5            67   H    H  H    H    H        O CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                                      C.sub.2                                                                        H.sub.5            68   CH.sub.3                                                                            H  H    H    H        O C.sub.2 H.sub.5                                                                         CH(CH.sub.3)CH.sub.2 CH.sub.2                                                  CO               C.sub.2                                                                        H.sub.5            69   CH.sub.3                                                                            CH.sub.3                                                                          H    H    H        O n--C.sub.3 H.sub.7                                                                      C(C.sub.2 H.sub.5).sub.2                                                       CH.sub.2 CH.sub.2 CO                                                                            C.sub.2                                                                        H.sub.5            70   CH.sub.3                                                                            CH.sub.3                                                                          n--C.sub.3 H.sub.7                                                                  H    H        O CH.sub.2 =CH                                                                            O(n--C.sub.3 H.sub.7).sub.2                                                    CH(n--C.sub.3 H.sub.7)CH.sub.2                                                 CO               C.sub.2                                                                        H.sub.5            71   H    H  H    H    H        O CH.sub.2 =CHCH.sub.2                                                           [C(CH.sub.3).sub.2 ].sub.2 CH.sub.2                                                     C.sub.2 H.sub.5                     72   H    H  C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     6--Cl    O CH.sub.2 =CH--                                                                          [C(C.sub.2 H.sub.5).sub.2                                                      ].sub.2 CH(C.sub.2 H.sub.5)CO                                                                   C.sub.2                                                                        H.sub.5            73   H    H  CH.sub.3                                                                            H    4--CH.sub.3                                                                             O HC.tbd.CH                                                                               [C(CH.sub.3).sub.2 ].sub.3                                                                      C.sub.2                                                                        H.sub.5                                   O                                                                              ∥                                              74   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                     H    5--OCCH.sub.3                                                                           O CH.sub.3 C.tbd.CH                                                                       CH(C.sub.2 H.sub.5)[C(C.sub.2                                                  H.sub.5)].sub.2 CO                                                                              C.sub.2                                                                        H.sub.5            75   H    H  CH.sub.3                                                                            CH.sub.3                                                                            7--OCH.sub.3                                                                            O          CH.sub.2 [C(CH.sub.3).sub.2                                                    ].sub.2 CO       C.sub.2                                                                        H.sub.5            76   H    H  H    H    4--Br    O          CH.sub.2 CH(CH.sub.3)C(CH.sub.3                                                ).sub.2 CO       C.sub.2                                                                        H.sub.5            77   CH.sub.3                                                                            CH.sub.3                                                                          H    H    4--n--C.sub.3 H.sub.7                                                                   O          CH.sub.2 CH.sub.2 C(C.sub.2                                                    H.sub.5).sub.2 CO                                                                               C.sub.2                                                                        H.sub.5            78   H    H  H    H    7--C.sub.2 H.sub.5                                                                      O          CH.sub.2 CH.sub.2 CH(CH.sub.3)C                                                O                C.sub.2                                                                        H.sub.5            79   CH.sub.3                                                                            CH.sub.3                                                                          CH.sub.3                                                                            H    5--F     O          [CH(CH.sub.3)].sub.3 CO                                                                         C.sub.2                                                                        H.sub.5            80   CH.sub.3                                                                            CH.sub.3                                                                          H    H    4--CH.sub.3                                                                             O          CH(C.sub.2 H.sub.5)CH.sub.2                                                    CH(C.sub.2 H.sub.5)CO                                                                           C.sub.2                                                                        H.sub.5            81   C.sub.2 H.sub.5                                                                     H  H    H    6--NO.sub.2                                                                             O --CH.sub.2                                                                              [CH(CH.sub.3)].sub.3 CO                                                                         C.sub.2                                                                        H.sub.5            82   CH.sub.3                                                                            CH.sub.3                                                                          H    H    4--n--C.sub..sub.3 CO                                                                   C.sub.2 H.sub.5                                82   CH.sub.3                                                                            CH.sub.3                                                                          H    H    4--n--C.sub.3 H.sub.7                                                                   O --CH.sub.2                                                                              CH.sub.2 [CH(C.sub.2 H.sub.5)].                                                sub.2 CO         C.sub.2                                                                        H.sub.5            83   H    H  H    H    7--OH    O --CH.sub.2                                                                              C(CH.sub.3).sub.2 CH.sub.2                                                     C(CH.sub.3).sub.2 CO                                                                            C.sub.2                                                                        H.sub.5            84   CH.sub.3                                                                            H  CH.sub.3                                                                            H    4--OC.sub.2 H.sub.5                                                                     O          [C(CH.sub.3).sub.2 ].sub.3                                                                      C.sub.2                                                                        H.sub.5            85   C.sub.2 H.sub. 5                                                                    H  C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     6--Cl    O          CH.sub.2 CH.sub.2 C(C.sub.2                                                    H.sub.5).sub.2 CO                                                                               C.sub.2                                                                        H.sub.5            86   CH.sub.3                                                                            CH.sub.3                                                                          CH.sub.3                                                                            CH.sub.3                                                                            4--Br    O          CH.sub.2 CH.sub.2 CH(CH.sub.3)C                                                O                C.sub.2                                                                        H.sub.5            EXAMPLE                                                                              PRODUCT: [(PREFIX LISTED BELOW)-1,3,4,9-TETRAHYDROPYRANO-[3,4-b]INDO           LE-1-(SUFFIX LISTED BELOW)]PREFIX//SUFFIX                                __________________________________________________________________________      4    1-methyl//carboxylic acid                                                 5    1-ethyl-3-methyl//carboxylic acid                                         6    1,3-diisopropyl-6-methyl//carboxylic acid                                 7    3,3-dimethyl-6-hydroxy 1-(1-propenyl)//carboxylic acid                    8    8-ethyl-1-ethynyl//carboxylic acid                                        9    1-cyclopropyl-4-isopropyl//carboxylic acid                               10    1-cyclopentyl-4,4-diethyl-3,3-dimethyl//carboxylic acid                  11    1-phenyl//carboxylic acid                                                12    1-benzyl-3-ethyl-3-methyl//carboxylic acid                               13    7-chloro-1-(2-thienyl)//carboxylic acid                                  14    1,4-dimethyl//acetic acid m.p. 163-164°C                          15    1-ethyl//acetic acid, m.p. 137-140°C.                             16    1-propyl//acetic acid m.p. 148-151°C.                             17    1-isopropyl//acetic acid, m.p. 150-152°C.                         18    1-allyl-3-methyl//acetic acid                                            19    3-methyl-1-propyl//acetic acid; m.p. 75-80°C. (Isomer A),               m.p. 146-148°C (Isomer B).                                        20    4-ethyl-1-ethynyl-3-methyl//acetic acid ν.sub.max.sup.CHCl.spsb.3            3300, 2135, 1710cm                                                      21    α,1-dimethyl//acetic acid; m.p. 154-156°C. (Isomer A),            m.p. 163-165°C. (Isomer B).                                       22    1-cyclohexyl-α,α -dimethyl//acetic acid                      23    1-phenyl//acetic acid, m.p. 148-150°C.                            24    1-t-butyl//acetic acid, m.p. 210-212°C.                           25    1-butyl//acetic acid m.p. 124-127°C                               26    8-methyl-1-propyl//acetic acid m.p. 127-128°C                     27    1-(2-thienyl)//acetic acid m.p. 127-130°C.                        28    6-bromo-1-ethyl//acetic acid m.p. 182-184°C.                      29    6-methoxy-1-methyl//acetic acid, m.p. 142-143°C.                  30    6-acetoxy-1-methyl//acetic acid, m.p. 142-143°C.                  31    6-benzyloxy-1-methyl//acetic acid, m.p. 163.5°C.                  32    5-methyl-1-propyl//acetic acid, m.p. 177-178°C.                   33    7-methyl-1-propyl//acetic acid, m.p. 157-158°C.                   34    6-nitro-1-propyl//acetic acid, m.p. 119-120°C.                    35    3,4-diisopropyl-α-methyl-6-nitro-1-vinyl//acetic acid              36    4,4-dimethyl-1-propyl//acetic acid, m.p. 184-185°C.               37    α,α-diisopropyl-4-ethyl-1-ethyhyl-8-methyl//acetic                 acid                                                                     38    1-cyclopropyl-α,α-diethyl-3,3-dimethyl-6-ethoxy//acetic            acid                                                                     39    1-cyclohexyl-α,α,3,3-tetramethyl-4,4-7-triethyl//acetic            acid                                                                     40    α,3-dimethyl-1-phenyl-4,4,5-tripropyl//acetic acid                 41    α,α-dimethyl-1-phenyl//acetic acid                           42    1-benzyl-α,α-diisopropyl-3,3,4,4,5-pentaethyl//acetic              acid                                                                     43    1-benzyl-8-propionoxy-α,α,3-trimethyl//acetic acid           44    α,4-dimethyl-1-(2-thienyl)//acetic acid                            45    α,α-dimethyl-1-(2-thienyl)//acetic acid                      46    5-iodo-1-isopropyl//propionic acid                                       47    8-acetoxy-α,3,3,4,4-pentamethyl-1-vinyl//propionic acid            48    β,β-diethyl-7-hydroxy-1-(2-propynyl)//propionic acid           49    1-cyclobutyl-3-methyl-8-nitro-α-propyl//propionic acid             50    α,α,β,β,4,6-hexamethyl-1-phenyl//propionic               acid                                                                     51    1-benzyl-8-bromo-α-ethyl-3-isopropyl-β-methyl//propionic            acid                                                                     52    8-chloro-3,4-diethyl-1-(2-thienyl)//propionic acid                       53    1,3-dimethyl-α,α-dipropyl//propionic acid                    54    4,4-diethyl-1-methallyl-α,α,β,5-tetramethyl//propio           nic acid                                                                 55    1-ethynyl-β,β,4,4-tetramethyl//propionic acid                  56    1-cyclopentyl-5-propionoxy-4-propyl-α,β,β-triethyl//           propionic acid                                                           57    5-methoxy-α-methyl-1-phenyl-3-propyl//propionic acid               58    1-benzyl-7-benzyloxy-α-ethyl-4-isopropyl//propionic acid           59    8-chloro-β,3,3,4,4-pentamethyl-1-(2-thienyl)//propionic acid        60    1-methyl-6-nitro-α,α-β,β,3-pentaethyl//propion           ic acid                                                                  61    1-allyl-6-fluoro-α-methyl-β,3,3-triethyl//propionic                 acid                                                                     62    β-propyl-1-(1-propynyl)-3,3,5-triethyl//propionic acid              63    1-cyclopropyl-α,β-diethyl-6-ethoxy//propionic acid            64    α,β,β,3,3,4,4-heptamethyl-1-phenyl-7-propoxy//propio           nic acid                                                                 65    1-benzyl-3,3-diethyl-α,α,β,β,6-pentamethyl//pr           opionic acid                                                             66    5-hydroxy-3-propyl-α,α,β,β-tetramethyl-1-(2-th           ienyl)//propionic acid                                                   67    1-methyl//butyric acid, m.p. 132-135°C.                           68    γ,3-dimethyl-1-ethyl//butyric acid                                 69    γ,γ-diethyl-3,3-dimethyl-1-propyl//butyric acid              70    3,3-dimethyl-β,γ,γ,4-tetrapropyl-1-vinyl//butyric             acid                                                                     71    1-allyl-β,β,γ,γ-tetramethyl//butyric acid          72    7-chloro-α,β,β,γ,γ-4-heptaethyl-1-vinyl/           /butyric acid                                                            73    1-ethynyl-α,α,β,β,γ,γ,-4,5-octamet           hyl//butyric acid                                                        74    6-acetoxy-α,α,β,β,γ,3,-3,4-octaethyl-1-(           1-propynyl)//butyric acid                                                75    1-cyclobutyl-α,α,β,β-4,4-hexamethyl-8-methoxy/           /butyric acid                                                            76    5-bromo-1-cyclopentyl-α,α,β-trimethyl//butyric                acid                                                                     77    1-cyclopropyl-α,α-diethyl-3,3-dimethyl-5-propyl//butyric            acid                                                                    78    8-ethyl-α-methyl-1-phenyl//butyric acid                            79    6-fluoro-α,β,γ,3,3,4-hexamethyl-1-phenyl//butyric             acid                                                                     λ                                                                             α,γ-diethyl-1-phenyl-3,3,5-trimethyl//butyric acid           81    1-benzyl-3-ethyl-7-nitro-α,β,γ-trimethyl//butyric             acid                                                                     82    1-benzyl-α,β-diethyl-3,3-dimethyl-5-propyl//butyric                 acid                                                                     83    1-benzyl-8-hydroxy-α,α,γ,γ-tetramethyl//buty           ric acid                                                                 84    5-ethoxy-α,α,β,β,γ,γ-3,4-octomethy           l-1-(2-thienyl)//butyric acid                                            85    7-chloro-α,α,3,4,4-pentaethyl-1-2-thienyl)//butyric                acid                                                                     86    5-bromo-α,3,3,4,4-pentamethyl-1-(2-thienyl)//butyric               __________________________________________________________________________           acid                                                                

                                      TABLE II                                     __________________________________________________________________________           STARTING MATERIAL OF        KETOESTER OF                                 EXAMPLE                                                                              FORMULA II                   FORMULA VI                                                                    O                                                                              ∥                                                                     (R.sup.1 --C--Y--OR.sup.16)                  R.sup.2    R.sup.3                                                                           R.sup.4                                                                             R.sup.5                                                                             R.sup.6 X R.sup.1  Y               R.sup.16            __________________________________________________________________________     87    H    H  H    H    H       S CH.sub.3 CO              C.sub.2                                                                        H.sub.5             88    CH.sub.3                                                                            H  H    H    H       S C.sub.2 H.sub.5                                                                         CO              C.sub.2                                                                        H.sub.5             89    i--C.sub.3 H.sub.7                                                                  H  H    H    5--CH.sub.3                                                                            S i--C.sub.3 H.sub.7                                                                      CO              CH.sub.3            90    CH.sub.3                                                                            CH.sub.3                                                                          H    H    5--OH   S CH.sub.3 CH=CH                                                                          CO              CH.sub.3            91    H    H  H    H    7--C.sub.2 H.sub.5                                                                     S HC=C     CO              CH.sub.3            92    H    H  i--C.sub.5 H.sub.7                                                                  H    H       S          CO              CH.sub.3            93    CH.sub.3                                                                            CH.sub.3                                                                          C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     H       S          CO              CH.sub.3            94    H    H  H    H    H       S          CO              CH.sub.3            95    CH.sub.3                                                                            C.sub.2 H.sub.5                                                                   H    H    H       S --CH.sub.2                                                                              CO              CH.sub.3            96    H    H  H    H    6--Cl   S          CO                                  97    H    H  CH.sub.3                                                                            H    H       S CH.sub.3 CH.sub.2 CO     C.sub.2                                                                        H.sub.5             98    H    H  H    H    H       S C.sub.2 H.sub.5                                                                         CH.sub.2 CO     C.sub.2                                                                        H.sub.5             99    H    H  H    H    H       S n--C.sub.3 H.sub.7                                                                      CH.sub.2 CO     C.sub.2                                                                        H.sub.5             100   H    H  H    H    H       S i--C.sub.3 H.sub.7                                                                      CH.sub.2 CO     C.sub.2                                                                        H.sub.5             101   CH.sub.3                                                                            H  H    H    H       S CH.sub.2 =CHCH.sub.2                                                                    CH.sub.2 CO     C.sub.2                                                                        H.sub.5             102   CH.sub.3                                                                            H  H    H    H       S n--C.sub.3 H.sub.7                                                                      CH.sub.2 CO     C.sub.2                                                                        H.sub.5             103   CH.sub.3                                                                            H  C.sub.2 H.sub.5                                                                     CH.sub.3                                                                            H       S HC.tbd.C CH.sub.2 CO     C.sub.2                                                                        H.sub.5             104   H    H  H    H    H       S CH.sub.3 CH(CH.sub.3)CO C.sub.2 H.sub.5      105   H    H  H    H    H       S          C(CH.sub.3).sub.2 CO                                                                           C.sub.2                                                                        H.sub.5             106   H    H  H    H    H       S          CH.sub.2 CO     C.sub.2                                                                        H.sub.5             107   H    H  H    H    H       S t--C.sub.4 H.sub.9                                                                      CH.sub.2 CO     C.sub.2                                                                        H.sub.5             108   H    H  H    H    H       S n--C.sub.4 H.sub.9                                                                      CH.sub.2 CO     C.sub.2                                                                        H.sub.5             109   H    H  H    H    7--CH.sub.3                                                                            S n--C.sub.3 H.sub.7                                                                      CH.sub.2 CO     C.sub.2                                                                        H.sub.5             110   H    H  H    H    H       S          CH.sub.2 CO     C.sub.2                                                                        H.sub.5             111   H    H  H    H    5--Br   S n--C.sub.3 H.sub.7                                                                      CH.sub.2 CO     C.sub.2                                                                        H.sub.5             112   H    H  H    H    5--OCH.sub.3                                                                           S CH.sub.3 CH.sub.2 CO     CH.sub.3            113   H    H  H    H    5--OCOCH.sub.3                                                                         S CH.sub.3 CH.sub.2 CO     C.sub.2                                                                        H.sub.5             114   H    H  H    H    5--benzyl-                                                                             S CH.sub.3 CH.sub.2 CO     C.sub.2                                                                        H.sub.5                                      oxy                                                   115   H    H  H    H    4--CH.sub.3                                                                            S n--C.sub.3 H.sub. 7                                                                     CH.sub.2 CO     C.sub.2                                                                        H.sub.5             116   H    H  H    H    6--CH.sub.3                                                                            S n--C.sub.3 H.sub.7                                                                      CH.sub.2 CO     C.sub.2                                                                        H.sub.5             117   H    H  H    H    7--F    S CH.sub.2 =CH                                                                            C(C.sub.2 H.sub.5).sub.2                                                                       C.sub.2                                                                        H.sub.5             118   i-- C.sub.3 H.sub.7                                                                 H  i-- C.sub.3 H.sub.7                                                                 H    5--NO.sub.2                                                                            S CH.sub.2 =CH                                                                            CH(CH.sub.3)CO  C.sub.2                                                                        H.sub.5             119   CH.sub.3                                                                            CH.sub.3                                                                          H    H    5--Cl   S CH.sub.3 C.tbd.C                                                                        CH(i--C.sub.3 H.sub.7)CO                                                                       C.sub.2                                                                        H.sub.5             120   H    H  C.sub.2 H.sub.5                                                                     H    7--CH.sub.3                                                                            S HC.tbd.C C(i-- C.sub.3 H.sub.7).sub.2                                                   CO              C.sub.2                                                                        H.sub.5             121   CH.sub.3                                                                            CH.sub.3                                                                          H    H    5--OC.sub.2 H.sub.5                                                                    S          CH(C.sub.2 H.sub.5)CO                                                                          C.sub.2                                                                        H.sub.5             122   CH.sub.3                                                                            CH.sub.3                                                                          C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     6--C.sub.2 H.sub.5                                                                     S          C(CH.sub.3).sub.2 CO                                                                           C.sub.2                                                                        H.sub.5             123   CH.sub.3                                                                            H  n--C.sub.3 H.sub.7                                                                  n-- C.sub.3 H.sub.7                                                                 4--n--C.sub.3 H.sub.7                                                                  S          CH(CH.sub.3)CO  C.sub.2                                                                        H.sub.5             124   H    H  H    H    H       S          C(CH.sub.3).sub.2 CO                                                                           C.sub.2                                                                        H.sub.5             125   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     4--C.sub.2 H.sub.5                                                                     S --CH.sub.2--                                                                            C(i--C.sub.3 H.sub.7).sub.2                                                                    C.sub.2                                                                        H.sub.5                                     O                                                                              ∥                                             126   CH.sub.3                                                                            H  H    H    7--OCC.sub.2 H.sub.5                                                                   S --CH.sub.2 --                                                                           C(CH.sub.3).sub.2 CO                                                                           C.sub.2                                                                        H.sub.5             127   H    H  CH.sub.3                                                                            H    H       S          CH(CH.sub.3)CO  C.sub.2                                                                        H.sub.5             128   H    H  H    H    H       S          C(CH.sub.3).sub.2 CO                                                                           C.sub.2                                                                        H.sub.5             129   H    H  H    H    H       S CH.sub.3 CH.sub.2 CH.sub.2 CO                                                                           C.sub.2                                                                        H.sub.5                                     O                                                                              ∥                                             130   CH.sub.3                                                                            CH.sub.3                                                                          CH.sub. 3                                                                           CH.sub.3                                                                            7--OCCH.sub.3                                                                          S CH.sub.2 =CH                                                                            CH.sub.2 CH(CH.sub.3)CO                                                                        C.sub.2                                                                        H.sub.5             131   H    H  H    H    6--OH   S HC.tbd.C--CH.sub.2                                                                      CH.sub.2 C(C.sub.2 H.sub.5).sub                                                .2 CO           C.sub.2                                                                        H.sub.5             132   CH.sub.3                                                                            H  H    H    7--NO.sub.2                                                                            S          CH(n--C.sub.3 H.sub.7)CH.sub.2                                                 CO              C.sub.2                                                                        H.sub.5             133   H    H  CH.sub.3                                                                            H    5--CH.sub.3                                                                            S          C(CH.sub.3).sub.2 C(CH.sub.3).s                                                ub.2 CO         C.sub.2                                                                        H.sub.5             134   i--C.sub.3 H.sub.7                                                                  H  H    H    7--Br   S --CH.sub.2                                                                              CH(CH.sub.3)CH(C.sub.2                                                         H.sub.5)CO      C.sub.2                                                                        H.sub.5             135   C.sub.2 H.sub.5                                                                     H  C.sub.2 H.sub.5                                                                     H    7--Cl   S          CH.sub.2 CH.sub.2 CH.sub.2                                                                     C.sub.2                                                                        H.sub.5             136   CH.sub.3                                                                            H  H    H    H       S CH.sub.3 CH.sub.2 C(n--C.sub.3 H.sub.7).                                                sub.2 CO        C.sub.2                                                                        H.sub.5             137   CH.sub.3                                                                            H  C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     H       S CH.sub.2 =C(CH.sub.3)CH.sub.2                                                           CH(CH.sub.3)C(CH.sub.3 ).sub.2                                                 CO              CH.sub.3            138   H    H  CH.sub.3                                                                            CH.sub.3                                                                            H       S HC.tbd.C C(CH.sub.3).sub.2 CH.sub.2                                                                     CH.sub.3                                    0                                                                              ∥                                             139   H    H  n--C.sub.3 H.sub.7                                                                  H    4--OCC.sub.2 H.sub.5                                                                   S          C(C.sub.2 H.sub.5).sub.2                                                       C(C.sub.2 H.sub.5)CO                                                                           CH.sub.3            140   n--C.sub.3 H.sub.7                                                                  H  H    H    4--OCH.sub.3                                                                           S          CH.sub.2 CH(CH.sub.3)CO                                                                        C.sub.2                                                                        H.sub.5             141   H    H  i--C.sub.3 H.sub.7                                                                  H    6--benzyl                                                                              S --CH.sub.2                                                                              CH.sub.2 CH)C.sub.2 H.sub.5)CO                                                                 C.sub.2                                                                        H.sub.5                                      oxy                                                   142   CH.sub.3                                                                            CH.sub.3                                                                          CH.sub.3                                                                            CH.sub.3                                                                            7--Cl   S          CH(CH.sub.3)CH.sub.2 CO                                                                        C.sub.2                                                                        H.sub.5             143   C.sub.2 H.sub.5                                                                     H  H    H    5--NO.sub.2                                                                            S CH.sub.3 CH(C.sub.2 H.sub.5).sub.2                                                      C(C.sub.2 H.sub.5).sub.2                                                                       C.sub.2                                                                        H.sub.5             144   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   H    H    5--F    S CH.sub.2 =CHCH.sub.2                                                                    CH(C.sub.2 H.sub.5)CH(CH.sub.3)                                                CO              C.sub.2                                                                        H.sub.5             145   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   H    H    4--C.sub.2 H.sub.5                                                                     S CH.sub.3 C=CH                                                                           C(n--C.sub.3 H.sub.7)CH.sub.2                                                  CO              CH.sub.3            146   H    H  H    H    6--OC.sub.2 H.sub.5                                                                    S          CH(C.sub.2 H.sub.5)CH(C.sub.2                                                  H.sub.5)CO      C.sub.2                                                                        H.sub.5             147   CH.sub.3                                                                            CH.sub.3                                                                          CH.sub.3                                                                            CH.sub.3                                                                            6--O--n--C.sub.3 H.sub.7                                                               S          C(CH.sub.3).sub.2 CH(CH.sub.3)C                                                O               C.sub.2                                                                        H.sub.5             148   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   H    H    5--CH.sub.3                                                                            S --CH.sub.2                                                                              C(CH.sub.3).sub.2 C(CH.sub.3).s                                                ub.2 CO         C.sub.2                                                                        H.sub.5             149   n--C.sub.3 H.sub.7                                                                  H  H    H    4--OH   S          C(CH.sub.3).sub.2 C(CH.sub.3).s                                                ub.2 CO         C.sub.2                                                                        H.sub.5             150   H    H  H    H    H       S CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                                     C.sub.2                                                                        H.sub.5             151   CH.sub.3                                                                            H  H    H    H       S C.sub.2 H.sub.5                                                                         CH(CH.sub.3)CH.sub.2 CH.sub.2                                                  CO              C.sub.2                                                                        H.sub.5             152   CH.sub.3                                                                            CH.sub.3                                                                          H    H    H       S n--C.sub.3 H.sub.7                                                                      C(C.sub.2 H.sub.5).sub.2                                                       CH.sub.2 CH.sub.2 CO                                                                           C.sub.2                                                                        H.sub.5             153   CH.sub.3                                                                            CH.sub.3                                                                          n--C.sub.3 H.sub.7                                                                  H    H       S CH.sub.2 =CH                                                                            O(n--C.sub.3 H.sub.7).sub.2                                                    CH(n--C.sub.3 H.sub.7)CH.sub.2                                                 CO              C.sub.2                                                                        H.sub.5             154   H    H  H    H    H         CH.sub.2 =CHCH.sub.2                                                                    [C(CH.sub.3).sub.2 ].sub.2                                                     CH.sub.2 CO     C.sub.2                                                                        H.sub.5             155   H    H  C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     6--Cl   S CH.sub.2 =CH                                                                            [C(C.sub.2 H.sub.5).sub.2                                                      ].sub.2 CH(C.sub.2 H.sub.5)CO                                                                  C.sub.2                                                                        H.sub.5             156   H    H  CH.sub.3                                                                            H    4--CH.sub.3                                                                            S HC.tbd.CH                                                                               [C(CH.sub.3).sub.2 ].sub.3                                                                     C.sub.2                                                                        H.sub.5                                     O                                                                              ∥                                             157   C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                     H    5--OCCH.sub.3                                                                          S CH.sub.3 C.tbd.CH                                                                       CH(C.sub.2 H.sub.5)[C(C.sub. 2                                                 H.sub.5)].sub.2 CO                                                                             C.sub.2                                                                        H.sub.5             158   H    H  CH.sub.3                                                                            CH.sub.3                                                                            7--OCH.sub.3                                                                           S          CH.sub.2 [C(CH.sub.3).sub.3                                                    ].sub.2 CO      C.sub.2                                                                        H.sub.5             159   H    H  H    H    4--Br   S          CH.sub.2 CH(CH.sub.3)C(CH.sub.3                                                ).sub.2 CO      C.sub.2                                                                        H.sub.5             160   CH.sub.3                                                                            CH.sub.3                                                                          H    H    4--n--C.sub.3 H.sub.7                                                                  S          CH.sub.2 CH.sub.2 C(C.sub.2                                                    H.sub.5).sub.2 CO                                                                              C.sub.2                                                                        H.sub.5             161   H    H  H    H    7--C.sub.2 H.sub.5                                                                     S          CH.sub.2 CH.sub.2 CH(CH.sub.3)C                                                O               C.sub.2                                                                        H.sub.5             162   CH.sub.3                                                                            CH.sub.3                                                                          CH.sub.3                                                                            H    5--F    S          [CH(CH.sub.3)].sub.3 CO                                                                        C.sub.2                                                                        H.sub.5             163   CH.sub.3                                                                            CH.sub.3                                                                          H    H    4--CH.sub.3                                                                            S          CH(C.sub.2 H.sub.5)CH.sub.2                                                    CH(C.sub.2 H.sub.5)CO                                                                          C.sub.2                                                                        H.sub.5             164   C.sub.2 H.sub.5                                                                     H  H    H    6--NO.sub.2                                                                            S  CH.sub.2                                                                               [CH(CH.sub.3)].sub.3 CO                                                                        C.sub.2                                                                        H.sub.5             165   CH.sub.3                                                                            CH.sub.3                                                                          H    H    4--n--C.sub.3 H.sub.7                                                                  S --CH.sub.2                                                                              CH.sub.2 [CH(C.sub.2 H.sub.5)].                                                sub.2 CO        C.sub.2                                                                        H.sub.5             166   H    H  H    H    7--OH   S --CH.sub.2                                                                              C(CH.sub.3).sub.2 CH.sub.2                                                     C(CH.sub.3).sub.2 CO                                                                           C.sub.2                                                                        H.sub.5             167   CH.sub.3                                                                            H  CH.sub.3                                                                            H    4--OC.sub.2 H.sub.5                                                                    S          [C(CH.sub.3).sub.2 ].sub.3                                                                     C.sub.2                                                                        H.sub.5             168   C.sub.2 H.sub.5                                                                     H  C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     6--Cl   S          CH.sub.2 CH.sub.2 C(C.sub.2                                                    H.sub.5).sub.2 CO                                                                              C.sub.2                                                                        H.sub.5             __________________________________________________________________________     EXAMPLE                                                                              PRODUCT: [(PREFIX LISTED BELOW)-1,3,4,9-TETRAHYDROTHIOPYRANO-[3,4-b]           INDOLE-1-(SUFFIX LISTED BELOW)]                                                PREFIX//SUFFIX                                                           __________________________________________________________________________     87    1-methyl//carboxylic acid                                                88    1-ethyl-3-methyl//carboxylic acid                                        89    1,3-diisopropyl-6-methyl//carboxylic acid                                90    3,3-dimethyl-6-hydroxy-1-(1-propenyl)carboxylic acid                     91    8-ethyl-1-ethynyl//carboxylic acid                                       92    1-cyclopropyl-4-iso-propyl//carboxylic acid                              93    1-cyclopentyl-4,4-diethyl-3,3-dimethyl//carboxylic acid                  94    1-phenyl//carboxylic acid                                                95    1-benzyl-3-ethyl-methyl//carboxylic acid                                 96    7-chloro-1-(2-thienyl)carboxylic acid                                    97    1,4-dimethyl//acetic acid                                                98    1-ethyl//acetic acid, m.p. 138°C.                                 99    1-propyl//acetic acid m.p. 127-129°C.                             100   1-isopropyl//acetic acid                                                 101   1-allyl-3-methyl//acetic acid                                            102   3-methyl-1-propyl//acetic acid                                           103   4-ethyl-1-ethynyl-3-methyl//acetic acid                                  104   α,1-dimethyl//acetic acid                                          105   1-cyclohexyl-α,α-dimethyl//acetic acid                       106   1-phenyl//acetic acid                                                    107   1-t-butyl//acetic acid                                                   108   1-butyl//acetic acid                                                     109   8-methyl-1-propyl//acetic acid                                           110   1-(2-thienyl)//acetic acid                                               111   6-bromo-1-propyl//acetic acid                                            112   6-methoxy-1-methyl//acetic acid                                          113   6-acetoxy-1-methyl//acetic acid                                          114   6-benzyloxy-1-methyl//acetic acid                                        115   5-methyl-1-propyl//acetic acid                                           116   7-methyl-1-propyl//acetic acid                                           117   α,α-diethyl-8-fluoro-1-vinyl//acetic acid                    118   3,4-diisopropyl-α-methyl-6-nitro-1-vinyl//acetic acid              119   6-chloro-3,3-dimethyl α-isopropyl-1-(1-propynyl)//acetic                 acid                                                                     120   α,α-diisopropyl-4-ethyl-1-ethynyl-8-methyl//acetic                 acid                                                                     121   1-cyclopropyl-α,α-diethyl-3,3-dimethyl-6-ethoxy//acetic            acid                                                                     122   1-cyclohexyl-α,α,3,3-tetramethyl-4,4,7-triethyl//acetic            acid                                                                     123   α,3-dimethyl-1-phenyl-4,4,5-tripropyl//acetic acid                 124   α,αdimethyl-1-phenyl//acetic acid                            125   1-benzyl-α,α-diisopropyl-3,3,4,4,5-pentaethyl//acetic              acid                                                                     126   1-benzyl-8-propionoxy-α,α,3-trimethyl//acetic acid           127   α,4-dimethyl-1-(2-thienyl)//acetic acid                            128   α,α-dimethyl-1-(2-thienyl)//acetic acid                      129   1-methyl//propionic acid                                                 130   8-acetoxy-α,3,3,4,4-pentamethyl-1-vinyl//propionic                 131   β,β-diethyl-7-hydroxy-1-(2-propynyl)//propionic acid           132   1-cyclobutyl-3-methyl-8-nitro-α-propyl//propionic acid             133   α,α,β,β4,6-hexamethyl-1-phenyl//propionic                acid                                                                     134   1-benzyl-8-bromo-α ethyl-3-isopropyl-βmethyl//propionic             acid                                                                     135   8-chloro-3,4-diethyl-1-(2-thienyl)//propionic acid                       136   1,3-dimethyl-α,α-dipropyl//propionic acid                    137   4,4-diethyl-1-methallyl-α,α,β,3-tetramethyl//propio           nic acid                                                                 138   1-ethynyl-β  ,β,4,4-tetramethyl//propionic acid                139   1-cyclopentyl-5-propionoxy-4-propyl-α,ββ-triethyl//p           ropionic acid                                                            140   5-methoxy-α-methyl-1-phenyl-3-propyl//propionic acid               141   1-benzyl-6-benzyloxy-α-ethyl-4-isopropyl//propionic acid           142   8-chloro-β,3,3,4,4-pentamethyl-1-(2-thienyl)//propionic acid        143   1-methyl-6-nitro-α,α-β,β,3-pentaethyl//propion           ic acid                                                                  144   1-allyl-6-fluoro-α-methyl-β,3,3-triethyl//propionic                 acid                                                                     145   β-propyl-1-(1-propynyl)-3,3,5-triethyl//propionic acid              146   1-cyclopropyl-α,β-diethyl-6-ethoxy//propionic acid            147   α,β,β3,3,4,4-heptamethyl-1-phenyl-7-propoxy//propion           ic acid                                                                  148   1-benzyl-3,3-diethyl-α,α,β,β,6-pentamethyl//pr           opionic acid                                                             149   5-hydroxy-3-propyl-α,α,β,β-tetramethyl-1-(2-th           ienyl)//propionic acid                                                   150   1-methyl//butyric acid                                                   151   γ,3-dimethyl-1-ethyl//butyric acid                                 152   γ,γ-diethyl-3,3-dimethyl-1-propyl//butyric acid              153   3,3-dimethyl-β,γ,γ,4-tetrapropyl-1-vinyl//butyric             acid                                                                     154   1-allyl-β,β,γ,γ-tetramethyl//butyric acid          155   7-chloro-α,β,β,γ,γ,4-4-heptaethyl-1-viny           l//butyric acid                                                          156   1-ethynyl-α,α,β,β,γ,γ,4,5-octameth           yl//butyric acid                                                         157   6-acetoxy-α,α,β,β,γ,3-3,4-octaethyl-1-(1           -propynyl)//butyric acid                                                 158   1-cyclobutyl-α,α,β,β,-4,4-hexamethyl-8-methoxy           ///butyric acid                                                          159   5-bromo-1-cyclopentyl-1-α,α,β-trimethyl//butyric              acid                                                                     160   1-cyclopropyl-α,α-diethyl-3,3-dimethyl-5-propyl//butyric            acid                                                                    161   8-ethyl-α-methyl-1-phenyl//butyric acid                            162   6-fluoro-α,β,γ,3,3,4-hexamethyl-1-phenyl//butyric             acid                                                                     163   αγ-diethyl-1-phenyl-3,3,5-trimethyl//butyric acid            164   1-benzyl-3-ethyl-7-nitro-α,β,γ-trimethyl//butyric             acid                                                                     165   1-benzyl-α,β-diethyl-3,3-dimethyl-5-propyl//butyric                 acid                                                                     166   1-benzyl-8-hydroxy-α,α,γ,γ-tetramethyl//buty           ric acid                                                                 167   5-ethoxy-α,αβ,β  ,γ,γ,-3,4-octomet           hyl-1-(2-thienyl)//butyric acid                                          168   7-chloro-α,α,3,4,4-pentaethyl-1-(2-thienyl)//butyric               acid                                                                     __________________________________________________________________________

EXAMPLE 169 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-CARBOXALDEHYDE (XI: R¹ = CH₃, R², R³, R⁴, R⁵ AND R⁶ = H, AND Y = CO)

A mixture of the starting material, tryptophol (32.2 g, 0.2 mole), acetonyl acetate (23.2 g, 0.2 mole) and 3.2 g of p-toluenesulfonic acid in 500 ml of benzene is refluxed for 11/2 hr. in the presence of a Dean-Stark water trap. The benzene solution is washed with 5% sodium bicarbonate, water, dried and evaporated to afford an oil. The oil is subjected to chromatography on a silica gel column using 10% ethyl acetate in benzene as eluent. The acetate, 1-methyl-1,3,4,9-tetrahydropryano[3,4-b]indole-1-methanol, acetate is obtained as an oil, nmr(CDCl₃) δ 1.52(S,3H), 2.08(S,3H), 4.35(2H).

This acetate is dissolved in 250 ml of methanol and stirred at room temperature. To this solution is added dropwise 20 ml of 10N NaOH. Hydrolysis is immediate. Most of the methanol is removed under reduced pressure, and water is added. The mixture is rendered neutral and extracted with chloroform. The chloroform extract is dried and evaporated to afford the primary alcohol, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole -1-methanol (X; R¹ = CH₃, R², R³, R⁴, R⁵ and R⁶ = H, Y = CH₂ and R¹⁷ = H), m.p. 145°-147°C., nmr(CDCl₃) δ 1.43(s,3H), 2.68(t, J = 5.5 cps,2H), 3.65 (d, J = 6 cps, 2H), 3.86 (t, J = 5.5 cps, 2H), after crystallization from benzene-petroleum ether.

N,N-dicyclohexylcarbodiimide (17.36 g. 0.084 mole) is added to a cooled, stirred solution of the above primary alcohol (6.09 g, 0.028 mole) in 63 ml of dimethyl sulfoxidebenzene (2:1) containing trifluoroacetic acid (1.12 ml, 0.014 mole) and pyridine (2.24 ml, 0.028 mole). The reaction is stirred at room temperature under nitrogen for 5 hr. The reaction mixture is now diluted with 600 ml of ether followed by the dropwise addition of a solution of oxalic acid (7.56 g) in 21 ml of methanol. After thirty minutes, water (600 ml) is added and the insoluble material is collected. The organic phase is washed with water (2X), 5% aqueous sodium bicarbonate (2X) and water (2X). After drying (MgSO₄) the organic phase is evaporated to yield an oil. The oil is purified by chromatography on silica gel. Elution with 10% ether in benzene affords the title compound as eluate, nmr (CDCl₃) δ 1.59(s,3H), 2.84(t,J = 5.5 cps, 2H), 4.15(t, J = 5.5 cps, 2H).

Oxidation of the latter compound with silver oxide according to the method of Delepine and Bonnet, cited above, affords 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxylic acid, nmr (CDCl₃) δ 1.79(s,3H), 2.83(t,2H), 4.17(t,2H), 9.20(1H), identical to the product obtained in Example 4.

By following the procedure of Example 169 but using as starting material an equivalent amount of the appropriate starting material of formula II, for example, those described in Examples 1 to 168, inclusive, instead of tryptophol, and using an equivalent amount of the appropriate ketoalcohol lower alkyl ester of formula VIII, then the acid compounds of formula I in which R⁷ is hydrogen and Z is hydroxy, for example, the respective products of Examples 1 to 168, inclusive, are obtained.

More specifically exemplified, according to the procedure of Example 169 the use of indole-3-ethanethiol and acetonyl acetate affords 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid, identical to the product of Example 3. Similarly, the use of tryptophol and 5-acetoxypentan-2-one affords 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid, identical to the product of Example 2.

EXAMPLE 170 N,N,1-TRIMETHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]-INDOLE-1-ACETAMIDE (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O, Y = CH₂ CO AND Z = N(CH₃)₂)

To a stirred solution of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (15 g, 0.061 mole), prepared as described in Example 1, in dry tetrahydrofuran (300 ml), cooled to -5°C, is added triethylamine (18.5 g,0.183 mole), followed by ethyl chloroformate (16.6 g, 0.153 mole). The mixture is stirred at -5°C for 2 hr. This mixture, which now contains the mixed anhydride of the above starting material, is added dropwise to a cooled 40% aqueous solution of the amine, dimethylamine (225 ml). The resulting mixture is stirred at room temperature for one-half hour. Most of the tetrahydrofuran is evaporated, and the residue partitioned between chloroform and water. The organic phase is washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is subjected to chromatography on silica gel. Elution with 20% ethyl acetate in benzene, followed by crystallization of the eluate from ethyl acetate affords the title compound, m.p. 149°-151°C., ν_(max) ^(CHCl).sbsp.3 3375, 1634 cm⁻ ¹.

In the same manner but replacing dimethylamine with an equivalent amount of ammonium hydroxide (concentrated), methylamine (30% aqueous solution), n-hexylamine (20% aqueous solution), diethylamine (30% aqueous solution), or aniline (20% aqueous solution),

1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 158°-160°C,

N,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 138°-140°C,

N-(hexyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N,n-diethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 99°C, and

N-phenyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 205°-208°C,

are obtained respectively.

by following the procedure of Example 170 but using as a starting material an equivalent amount of one of the acid compounds of formula I, described in Examples 2 to 168, inclusive, instead of 1-methyl-1,3,4,9-tetrahydropyrano[ 3,4-b]indole-1-acetic acid, and using an equivalent amount of an appropriate amine such as ammonia or a primary or secondary amine described in Example 170, then the corresponding amide compound of formula I [Z = NH₂, ##EQU7## NHCH₃, N(CH₃)₂, NH(n-C₆ H₁₃) or N(C₂ H₅)₂ ] is obtained. Examples of such amides are listed as products in Tables III and IV together with the appropriate starting material and amine used for the preparation of the amide. In each case the starting material is noted by the example in which it is prepared.

                                      TABLE III                                    __________________________________________________________________________         NO. OF THE EXAMPLE   PRODUCT: [(PREFIX LISTED BELOW-                           IN WHICH STARTING    1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                          MATERIAL IS          INDOLE-1-(SUFFIX LISTED BELOW)]                       EXAMPLE                                                                            PREPARED   AMINE          PREFIX//SUFFIX                                   __________________________________________________________________________     171 2          CH.sub.3 NH.sub.2                                                                        N,1-dimethyl//propionamide,                                                    m.p. 149-150°C.                                172 2          NH.sub.3  1-methyl//propionamide                                173 2          (CH.sub.3).sub.2 NH                                                                      N,N,1-trimethyl//propionamide                         174 2          n--C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-methyl//propionamide                        175 2          (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-1-methyl//propionamide                    176 4          CH.sub.3 NH.sub.2                                                                        N,1-dimethyl//carboxamide                             177 4          NH.sub.3  1-methyl//carboxamide, m.p. 188-                                               189°C.                                         178 4          (CH.sub.3).sub.2 NH                                                                      N,N,1-trimethyl//carboxamide                          179 4          n--C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-methyl//carboxamide                         180 4          (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-1-methyl//carboxamide                     181 5          CH.sub.3 NH.sub.2                                                                        N,3-dimethyl-1-ethyl//carboxamide                     182 8                    8-ethyl-1-ethynyl-N-phenyl//                                         --NH.sub.2                                                                               carboxamide                                           183 9          (CH.sub.3).sub.2 NH                                                                      1-cyclopropyl-N,N-dimethyl-4-iso-                                              propyl//carboxamide                                   184 11         n--C.sub.16 H.sub.13 NH.sub.2                                                            N-hexyl-1-phenyl//carboxamide                         185 12         (C.sub.2 H.sub.5).sub.2 NH                                                               1-benzyl-3-methyl-N,N,3-tri-                                                   ethyl//carboxamide                                    186 14         (CH.sub. 3).sub.2 NH                                                                     N,N,1,4-tetramethyl//acetamide                        187 15         CH.sub.3 NH.sub.2                                                                        1-ethyl-N-methyl//acetamide                           188 15         NH.sub.3  1-ethyl//acetamide                                    189 15         (CH.sub.3).sub.2 NH                                                                      N,N-dimethyl-1-ethyl//acetamide                       190 15         n--C.sub.16 H.sub.13 NH.sub.2                                                            1-ethyl-N-hexyl//acetamide                            191 15         (C.sub.2 H.sub.5).sub.2 NH                                                               N,N,1-triethyl//acetamide                             192 16         CH.sub.3 NH.sub.2                                                                        N-methyl-1-propyl//acetamide                          193 16         NH.sub.3  1-propyl//acetamide                                   194 16         (CH.sub.3).sub.2 NH                                                                      N,N-dimethyl-1-propyl//acetamide                      195 16         n--C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-propyl//acetamide                           196 16         (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-1-propyl//acetamide                       197 17         CH.sub.3 NH.sub.2                                                                        1-isopropyl-N-methyl//acetamide                       198 17         NH.sub.3  1-isopropyl//acetamide                                199 17         (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-1-isopropyl//acetamide                    200 19         CH.sub.3 NH.sub.2                                                                        N,3-dimethyl-1-propyl//acetamide                                               3-methyl-N-phenyl-1-propyl//                          201 19         --NH.sub.2                                                                               acetamide                                             202 19         (CH.sub.3).sub.2 NH                                                                      1-propyl-N,N,3-trimethyl//acetamide                   203 19         n--C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-3-methyl-1-propyl//                                                    acetamide                                             204 19         (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-3-methyl-1-propyl//                                                acetamide                                             205 21         CH.sub.3 NH.sub.2                                                                        N,α,1-trimethyl//acetamide                      206 21         NH.sub.3  α,1-dimethyl//acetamide                         207 21         (CH.sub.3).sub.2 NH                                                                      N,N,α,1-tetramethyl//acetamide                  208 21         n--C.sub.6 H.sub.13 NH.sub.2                                                             α,1-dimethyl-N-hexyl//acetamide                 209 21         (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-α,1-dimethyl//                                               acetamide                                             210 22         CH.sub.3 NH.sub.2                                                                        1-cyclohexyl-N,α,α-trimethyl//                                     acetamide                                             211 23         (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-1-phenyl//acetamide                       212 26         CH.sub.3 NH.sub.2                                                                        N,8-dimethyl-1-propyl//acetamide                      213 31         NH.sub.2  6-benzyloxy-1-methyl//acetamide                       214 32         (CH.sub.3).sub.2 NH                                                                      1-propyl-N,N,5-trimethyl//                                                     acetamide                                             215 38         n--C.sub.6 H.sub.13 NH.sub.2                                                             1-cyclopropyl-α,α-diethyl-3,3-                                     dimethyl-6-ethoxy-N-hexyl//                                                    acetamide                                             216 43         (CH.sub.3).sub.2 NH                                                                      1-benzyl-N,N,α,α,3-pentamethyl-                                    8-propionoxy//acetamide                               217 46         CH.sub.3 NH.sub.2                                                                        5-iodo-1-isopropyl-N-methyl//                                                  propionamide                                          218 49         NH.sub.2  1-cyclobutyl-3-methyl-8-nitro-                                                 α-propyl//propionamide                          219 54         (CH.sub.3).sub.2 NH                                                                      4,4-diethyl-N,N,α,α,β,3-hexa-                                 methyl-1-methallyl//propionamide                      220 57         (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-5-methoxy-60 -methyl-                                              1-phenyl-3-propyl//propionamide                       221 62         CH.sub.3 NH.sub.2                                                                        N-methyl-β-propyl-1-(1-propynyl)-                                         3,3,5-triethyl//propionamide                                                   1-cyclopropyl-α,β-diethyl-6-               222 63         --NH.sub.2                                                                               ethoxy-N-phenyl//propionamide                         223 67         (CH.sub.3).sub.2 NH                                                                      N,N,1-trimethyl//butyramide                           224 67         CH.sub.3 NH.sub.2                                                                        N,1-dimethyl//butyramide                              225 67         NH.sub.2  1-methyl//butyramide                                  226 67         n--C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-methyl//butyramide                          227 70         CH.sub.3 NH.sub.2                                                                        β,γ,γ,4-tetrapropyl-N,3,3-                                    trimethyl-1-vinyl//butyramide                         228 71         (C.sub.2 H.sub.5).sub.2 NH                                                               1-allyl-N,N-diethyl-β,β,                                             γ,γ-                                                               tetramethyl//butyramide                               229 73         (CH.sub.3).sub.2 NH                                                                      N,N,α,α,β,β,γ,γ                              ,4,5-decamethyl-                                                               1-ethynyl//butyramide                                 230 76         NH.sub.2  5-bromo-1-cyclopentyl-α,α,β-                                  trimethyl//butyramide                                 231 78         CH.sub.3 NH.sub.2                                                                        8-ethyl-N,α-dimethyl-1-phenyl//                                          butyramide                                            232 80         (C.sub.2 H.sub.5).sub.2 NH                                                               1-phenyl-N,N,α,γ-tetraethyl-                                       3,3,5-trimethyl//butyramide                           233 82         n--C.sub.6 H.sub.13 NH.sub.2                                                             1-benzyl-α,β-diethyl-3,3,-                                          dimethyl-N-hexyl-5-propyl//                                                    butyramide                                            __________________________________________________________________________

                                      TABLE IV                                     __________________________________________________________________________           NO. OF THE EXAMPLE    PRODUCT: [(PREFIX LISTED BELOW-                          IN WHICH STARTING     1,3,4,9-TETRAHYDROTHIOPYRANO-                            MATERIAL IS           [3,4-b]INDOLE-1-(SUFFIX LISTED                     EXAMPLE                                                                              PREPARED    AMINE     BELOW)] PREFIX//SUFFIX                             __________________________________________________________________________     234   3           CH.sub.3 NH.sub.2                                                                        N,1-dimethyl//acetamide                            235   3           NH.sub.2  1-methyl//acetamide                                236   3           n--C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-methyl//acetamide                        237   3           (CH.sub.3).sub.2 NH                                                                      N,N,1-trimethyl//acetamide                         238   3           (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-1-methyl//acetamide                    239   129         CH.sub.3 NH.sub.2                                                                        N,1-dimethyl//propionamide                         240   129         NH.sub.3  1-methyl//propionamide                             241   129         (CH.sub.3).sub.2 NH                                                                      N,N,1-trimethyl//propionamide                      242   129         n--C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-methyl//propionamide                     243   129         (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-1-methyl//propion-                                                 amide                                              244   87          CH.sub.3 NH.sub.2                                                                        N,1-dimethyl//carboxamide                          245   87          NH.sub.3  1-methyl//carboxamide,                             246   87          (CH.sub.3).sub.2 NH                                                                      N,N,1-trimethyl//carboxamide                       247   87          n--C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-methyl//carboxamide                      248   87          (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-1-methyl//carboxamide                  249   88          CH.sub.3 NH.sub.2                                                                        N,3-dimethyl-1-ethyl//carboxamide                  250   91          NH.sub.3  8-ethyl-1-ethynyl//carboxamide                     251   92          (CH.sub.3).sub.2 NH                                                                      1-cyclopropyl-N,N-dimethyl-4-iso-                                              propyl//carboxamide                                252   94          n--C.sub.16 H.sub.13 NH.sub.2                                                            N-hexyl-1-phenyl//carboxamide                      253   95          (C.sub.2 H.sub.5).sub.2 NH                                                               1-benzyl-3-methyl-N,N,3-tri-                                                   ethyl//carboxamide                                 254   97          (CH.sub.3).sub.2 NH                                                                      N,N,1,4-tetramethyl//acetamide                     255   98          CH.sub.3 NH.sub.2                                                                        1-ethyl-N-methyl//acetamide                        256   98          NH.sub.3  1-ethyl//acetamide                                 257   98          (CH.sub.3).sub.2 NH                                                                      N,N-dimethyl-1-ethyl//acetamide                    258   98          n--C.sub.16 H.sub.13 NH.sub.2                                                            1-ethyl-N-hexyl//acetamide                         259   98          (C.sub.2 H.sub.5).sub.2 NH                                                               N,N,1-triethyl//acetamide                          260   99          CH.sub.3 NH.sub.2                                                                        N-methyl-1-propyl//acetamide                       261   99          NH.sub.3  1-propyl//acetamide                                262   99          (CH.sub.3).sub.2 NH                                                                      N,N-dimethyl-1-propyl//acetamide                   263   99          n--C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-propyl//acetamide                        264   99          (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-1-propyl//acetamide                    265   100         CH.sub.3 NH.sub.2                                                                        1-isopropyl-N-methyl//acetamide                    266   100         NH.sub.3  1-isopropyl//acetamide                             267   100         (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-1-isopropyl//acetamide                 268   102         CH.sub.3 NH.sub.2                                                                        N,3-dimethyl-1-propyl//acetamide                   269   102         NH.sub.3  3-methyl-1-propyl//acetamide                       270   102         (CH.sub.3).sub.2 NH                                                                      1-propyl-N,N,3-trimethyl//                                                     acetamide                                          271   102         n--C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-3-methyl-1-propyl//                                                    acetamide                                          272   102         (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-3-methyl-1-propyl//                                                acetamide                                          273   104         CH.sub.3 NH.sub.2                                                                        N,α,1-trimethyl//acetamide                   274   104         NH.sub.3  α,1-dimethyl//acetamide                      275   104         (CH.sub.3).sub.2 NH                                                                      N,N,α,1-tetramethyl//acetamide               276   104         n--C.sub.6 H.sub.13 NH.sub.2                                                             α,1-dimethyl-N-hexyl//acetamide              277   104         (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-α,1-dimethyl//                                               acetamide                                          278   105         CH.sub.3 NH.sub.2                                                                        1-cyclohexyl-N,α,α-trimethyl//                                     acetamide                                          279   106         (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-1-phenyl//acetamide                    280   109         CH.sub.3 NH.sub.2                                                                        N,8-dimethyl-1-propyl//acetamide                   281   111         NH.sub.2  6-bromo-1-propyl//acetamide                        282   117         (CH.sub.3).sub.2 NH                                                                      α,α-diethyl-N,N-dimethyl-8-fluoro-                                 1-vinyl//acetamide                                 283   121         n--C.sub.6 H.sub.13 NH.sub.2                                                             1-cyclopropyl-α,α-diethyl-3,3-                                     dimethyl-6-ethoxy-N-hexyl//                                                    acetamide                                          284   126         (CH.sub.3).sub.2 NH                                                                      1-benzyl-N,Nα,α,3-pentamethyl-                                     8-propionoxy//acetamide                            285   128         CH.sub.3 NH.sub.2                                                                        1-(2-thienyl)-N,α,α-trimethyl//                                    acetamide                                          286   132         NH.sub.2  1-cyclobutyl-3-methyl-8-nitro-                                                 α-propyl//propionamide                       287   137         (CH.sub.3).sub.2 NH                                                                      4,4-diethyl-N,N,α,α,β,3-                                      hexamethyl-1-methallyl//                                                       propionamide                                       288   140         (C.sub.2 H.sub.5).sub.2 NH                                                               N,N-diethyl-5-methoxy-α-methyl-1-                                        phenyl-3-propyl//propionamide                      289   145         CH.sub.3 NH.sub.2                                                                        N-methyl-β-propyl-1-(1-propynyl)-                                         3,3,5-triethyl//propionamide                       290   146         --NH.sub.2                                                                               1-cyclopropyl-α,β-diethyl-6-                                        ethoxy-N-phenyl//propionamide                      291   150         (CH.sub.3).sub. 2 NH                                                                     N,N,1-trimethyl//butyramide                        292   150         CH.sub.3 NH.sub.2                                                                        N,1-dimethyl//butyramide                           293   150         --NH.sub.2                                                                               1-methyl-N-phenyl//butyramide                      294   150         n--C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-methyl//butyramide                       295   153         CH.sub.3 NH.sub.2                                                                        β,γ,γ,4-tetrapropyl-N,3,3-                                    trimethyl-1-vinyl//butyramide                      296   154         (C.sub.2 H.sub.5).sub.2 NH                                                               1-allyl-N,N-diethyl-β,β,γ,.gam                                 ma.-                                                                           tetramethyl//butyramide                            297   155         (CH.sub.3).sub.2 NH                                                                      7-chloro-N,N-dimethyl-α,β,β,.g                                 amma.,γ-                                                                 4,4-heptaethyl-1-ethynyl//butyramide               298   159         NH.sub.2  5-bromo-1-cyclopentyl-α,α,β-                                  trimethyl//butyramide                              299   161         CH.sub.3 NH.sub.2                                                                        N,α-dimethyl-8-ethyl-1-phenyl//                                          butyramide                                         300   163         (C.sub.2 H.sub.5).sub.2 NH                                                               1-phenyl-N,N,α,γ-tetraethyl-                                       3,3,5-trimethyl//butyramide                        301   165         n--C.sub.6 H.sub.13 NH.sub.2                                                             1-benzyl-α,β-diethyl-3,3-dimethyl-                                  N-hexyl-5-propyl//butyramide                       302   168         CH.sub.3 NH.sub.2                                                                        7-chloro-N-methyl-α,α,3,4,4-                                       pentaethyl-1-(2-thienyl)//                                                     butyramide                                         __________________________________________________________________________

EXAMPLE 303 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-CARBOXAMIDE (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O, Y = CO AND Z = NH₂)

By following the procedure of Example 1 but using an equivalent amount of pyruvamide instead of ethyl acetoacetate, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxamide, m.p. 188°-189°C. after recrystallization from benzene-hexane, identical with the product of Example 177, is obtained.

In the same manner but using an equivalent amount of the appropriate starting material of formula II in place of tryptophol together with the appropriate α-, β-, γ- or δ-ketoamide, the products listed in Tables III and IV may be obtained. For example, by using tryptophol (II; R², R³, R⁴, R⁵, R⁶ = H and X' = OH) and the β-ketoamide, N,N-dimethyl-acetoacetamide, in the procedure of this Example, N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, identical with the product of Example 170, is obtained.

EXAMPLE 304 1,9-DIMETHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-ACETIC ACID (I; R¹ and R⁷ = CH₃, R², R³, R⁴, R⁵ AND R⁶ = H, X = O, Y = CH₂ CO AND Z = OH

1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (10 g., 0.04 mole), prepared as described in Example 1, in 150 ml. of tetrahydrofuran is added dropwise to a stirred suspension of sodium hydride (4.4 g. of 55% dispresion in 200 ml. of tetrahydrofuran. This mixture is heated at 50°C. with stirring for 2 hr. Methyl iodide (14.2 g. 0.1 mole) is added dropwise and heating and stirring is continued for a further 2 hr.

After cooling, water is added until the solution is clear. The tetrahydrofuran is evaporated off under reduced pressure, the residue is partition between water and benzene. The aqueous phase is washed once with benzene, made acidic with HCl, and extracted with benzene (3×). The organic phase is washed with water, dried over sodium sulfate and treated with charcoal. The organic layer is evaporated. The residue is crystallized from benzene and then ether-petroleum ether to afford the title compound, m.p. 105°- 108°C., nmr (CDCl.sub. 3) δ 1.73 (S,3H), 2.83 (t, J = 5.5, 2H), 3.0 (2H), 3.68 (3H), 4.08 (t, J = 5.5, 2H), 7.34 (4H), 9.47 (1H).

In the same manner but replacing methyl iodide with an equivalent amount of ethyl iodide, or propyl iodide 9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, m.p. 134°-136°C., and 1-methyl-9-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, m.p. 120°-122°C., are obtained, respectively.

By following the procedure of Example 304 but using the starting material an equivalent amount of the acid compounds of formula I, compounds of formula I in which R⁷ is hydrogen and Z is hydroxy, described in Examples 1 to 168, inclusive, instead of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and using an equivalent amount of an appropriate lower alkyl or lower alkenyl halide, then the corresponding N-alkylated acid compounds of formula I in which R⁷ is lower alkyl or lower alkenyl are obtained. Examples of these latter compounds are listed as products in Tables V and VI together with the appropriate starting material and alkyl or alkynl halide used for their preparation. In each case the starting material is noted by the Example in which it is prepared.

                                      TABLE V                                      __________________________________________________________________________            NO. OF THE EXAMPLE        PRODUCT: [(PREFIX LISTED BELOW-                      IN WHICH STARTING         1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                     MATERIAL IS  ALKYL OR ALKENYL                                                                            INDOLE-1-(SUFFIX LISTED BELOW)]               EXAMPLE                                                                               PREPARED       HALIDE       PREFIX//SUFFIX                              __________________________________________________________________________     305     1           CH.sub.2 =CHCH.sub.2 Br                                                                     9-allyl-1-methyl//acetic acid,                                                 m.p.103 - 105°C.                       306     1           CH.sub.2 =CHBr                                                                              1-methyl-9-vinyl//acetic acid                 307     1           CH.sub.2 =C(CH.sub.3)CH.sub.2 Br                                                            1-methyl-9-methallyl//acetic acid             308     2           n--C.sub.3 H.sub.7 I                                                                        1-methyl-9-propyl//propionic acid             309     2           CH.sub.3 I   1,9-dimethyl//propionic acid                  310     2           CH.sub.2 =CHBr                                                                              1-methyl-9-vinyl//propionic acid              311     2           CH.sub.2 =CHCH.sub.2 Cl                                                                     9-allyl-1-methyl//propionic acid              312     4           CH.sub.3 I   1,9-dimethyl//carboxylic acid                 313     4           CH.sub.2 =CHBr                                                                              1-methyl-9-vinyl//carboxylic acid             314     7           CH.sub.3 I   6-hydroxy-1-(1-propenyl)-3,3,9-                                                trimethyl//carboxylic acid                    315     9           CH.sub.3 CH=CHBr                                                                            1-cyclopropyl-4-isopropyl-9-                                                   (1-propenyl)//carboxylic acid                 316    11           i--C.sub.3 H.sub.7 I                                                                        9-isopropyl-1-phenyl//carboxylic                                               acid                                          317    15           CH.sub.3 I   1-ethyl-9-methyl//acetic acid                 318    15           C.sub.2 H.sub.5 Cl                                                                          1,9-diethyl//acetic acid                      319    15           CH.sub.2 =CHCH.sub.2 Br                                                                     9-allyl-1-ethyl//acetic acid                  320    15           CH.sub.2 =CHBr                                                                              1-ethyl-9-vinyl//acetic acid                  321    16           CH.sub.3 I   9-methyl-1-propyl//acetic acid                322    16           n--C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl//acetic acid                     323    16           CH.sub.2 =CHCH.sub.2 Br                                                                     9-allyl-1-propyl//acetic acid                 324    16           CH.sub.2 =C(CH.sub.3)CH.sub.2 Br                                                            9-methallyl-1-propyl//acetic acid             325    17           CH.sub.3 I   9-methyl-1-isopropyl//acetic acid             326    17           CH.sub.2 =CHBr                                                                              1-isopropyl-9-vinyl//acetic acid              327    19           n--C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl-3-methyl//acetic acid            328    19           CH.sub.2 =CHCH.sub.2 Br                                                                     9-allyl-3-methyl-1-propyl//acetic                                              acid                                          329    21           CH.sub.3 I   α,1,9-trimethyl//acetic acid            330    21           CH.sub.2 =CHBr                                                                              α,1-dimethyl-1-vinyl//acetic acid       331    22           n--C.sub.3 H.sub.7 Cl                                                                       1-cyclohexyl-α,α-dimethyl-9-                                       propyl//acetic acid                           332    27           CH.sub.2 =CHCH.sub.2 I                                                                      9-allyl-1-(2-thienyl)//acetic acid            333    29           CH.sub.3 Cl  1,9-dimethyl-61methoxy//acetic acid           334    34           CH.sub.2 =CHBr                                                                              6-nitro-1-propyl-9-vinyl//                                                     acetic acid                                   335    40           C.sub.2 H.sub.5 Cl                                                                          α,3-dimethyl-9-ethyl-1-phenyl-                                           4,4,5-tripropyl//acetic acid                  336    42           CH.sub.2 =CHCH.sub.2 Br                                                                     9-allyl-1-benzyl-α,α-diisopro                                      pyl-                                                                           3,3,4,4,5-pentaethyl//acetic acid             337    48           C.sub.2 H.sub.5 I                                                                           7-hydroxy-1-(2-propynyl)-β,β,9-                                      triethyl//propionic acid                      338    49           CH.sub.3 I   1-cyclobutyl-3,9-dimethyl-8-nitro-                                             α-propyl//propionic acid                339    54           CH.sub.2 =C(CH.sub.3)CH.sub.2 Cl                                                            4,4-diethyl-1,9-dimethallyl-α,.alph                                      a.,β,-                                                                    3-tetramethyl//propionic acid                 340    59           CH.sub.2 =CHCH.sub.2 Br                                                                     9-allyl-8-chloro-β,3,3,4,4-                                               pentamethyl-1-(2-thienyl)//                                                    propionic acid                                341    60           CH.sub.2 =CHCl                                                                              1-methyl-6-nitro-α,α,β,.                                      beta.,3-penta-                                                                 ethyl-9-vinyl//propionic acid                 342    63           C.sub.2 H.sub.5 Cl                                                                          1-cyclopropyl-6-ethoxy-α,β,9-                                       triethyl//propionic acid                      343    67           CH.sub.3 I   1,9-dimethyl//butyric acid                    344    67           CH.sub.2 =CHCH.sub.2 Cl                                                                     9-allyl-1-methyl//butyric acid                345    68           C.sub.2 H.sub.5 Cl                                                                          1,9-diethyl-γ,3-dimethyl//butyric                                        acid                                          346    70           CH.sub.2 =CHBr                                                                              3,3-dimethyl-1,9-divinyl-β,γ,.                                      gamma.,-                                                                       4-tetrapropyl//butyric acid                   347    72           CH.sub.2 =CHBr                                                                              7-chloro-1,9-divinyl-α,β,.beta                                      .,γ,γ,-                                                            4-heptaethyl//butyric acid                    348    78           C.sub.2 H.sub.5 I                                                                           8,9-diethyl-α-methyl-1-phenyl//                                          butyric acid                                  349    82           CH.sub.3 I   1-benzyl-α,β-diethyl-5-propyl-                                      3,3,9-trimethyl//butyric acid                 350    85           C.sub.2 H.sub.5 Br                                                                          7-chloro-α,α,3,4,4,9-hexaethy                                      l-                                                                             1-(2-thienyl)//butyric                        __________________________________________________________________________                                      acid                                     

                                      TABLE VI                                     __________________________________________________________________________           NO. OF THE EXAMPLE       PRODUCT:[(PREFIX LISTED BELOW-1,3,-                   IN WHICH STARTING        4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                      MATERIAL IS  ALKYL OR ALKENYL                                                                           INDOLE-1-(SUFFIX LISTED BELOW)]                 EXAMPLE                                                                              PREPARED       HALIDE      PREFIX//SUFFIX                                __________________________________________________________________________     351   3            CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-methyl//acetic acid                   352   3            CH.sub.3 I  1,9-dimethyl//acetic acid                       353   3            CH.sub.2 =C(CH.sub.3)CH.sub.2 Br                                                           1-methyl-9-methallyl//acetic                                                   acetic acid                                     354   129          n--C.sub.3 H.sub.7 I                                                                       1-methyl-9-propyl//propionic                                                   acid                                            355   129          CH.sub.3 I  1,9-dimethyl//propionic acid                    356   129          CH.sub.2 =CHBr                                                                             1-methyl-9-vinyl//propionic acid                357   129          CH.sub.2 =CHCH.sub.2 Cl                                                                    9-allyl-1-methyl//propionic acid                358   87           CH.sub.3 I  1,9-dimethyl//carboxylic acid                   359   87           CH.sub.2 =CHBr                                                                             1-methyl-9-vinyl//carboxylic                                                   acid                                            360   90           CH.sub.3 I  6-hydroxy-1-(1-propenyl)-3,3,9-                                                trimethyl//carboxylic acid                      361   92           CH.sub.3 CH=CHBr                                                                           1-cyclopropyl-4-isopropyl-9-                                                   (1-propenyl)//carboxylic acid                   362   94           2--C.sub.3 H.sub.7 I                                                                       9-isopropyl-1-phenyl//carboxylic                                               acid                                            363   98           CH.sub.3 I  1-ethyl-9-methyl//acetic acid                   364   98           C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl//acetic acid                        365   98           CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-ethyl//acetic acid                    366   98           CH.sub.2 =CHBr                                                                             1-ethyl-9-vinyl//acetic acid                    367   99           CH.sub.3 I  9-methyl-1-propyl//acetic acid                  368   99           n--C.sub.3 H.sub.7 Cl                                                                      1,9-dipropyl//acetic acid                       369   99           CH.sub.2 CHCH.sub.2 Br                                                                     9-allyl-1-propyl//acetic acid                   370   99           CH.sub.2 =C(CH.sub.3)CH.sub.2 Br                                                           9-methallyl-1-propyl//acetic                                                   acid                                            371   100          CH.sub.3 I  9-methyl-1-isopropyl//acetic                                                   acid                                            372   100          CH.sub.2 =CHBr                                                                             1-isopropyl-9-vinyl//acetic                                                    acid                                            373   102          n--C.sub.3 H.sub.7 Cl                                                                      1,9-dipropyl-3-methyl//acetic                                                  acid                                            374   102          CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-3-methyl-1-propyl//                                                    acetic acid                                     375   104          CH.sub.3 I  α,1,9-trimethyl//acetic acid              376   104          CH.sub.2 =CHBr                                                                             α,1-dimethyl-1-vinyl//acetic                                             acid                                            377   105          n--C.sub.3 H.sub.7 Cl                                                                      1-cyclohexyl-α,α-dimethyl-9-                                       propyl//acetic acid                             378   110          CH.sub.2 =CHCH.sub.2 I                                                                     9-allyl-1-(2-thienyl)//acetic                                                  acid                                            379   112          CH.sub.3 Cl 1,9-dimethyl-6-methoxy//                                                       acetic acid                                     380   117          CH.sub.2 CHBr                                                                              α,α-diethyl-1,9-divinyl-8-                                         fluoro//acetic acid                             381   123          C.sub.2 H.sub.5 Cl                                                                         α,3-dimethyl-9-ethyl-1-phenyl-                                           4,4,5-tripropyl//acetic                                                        acid                                            382   125          CH.sub.2 CHCH.sub.2 Br                                                                     9-allyl-1-benzyl-α,α-                                              diisopropyl-3,3,4,4,5-                                                         pentaethyl//acetic acid                         383   131          C.sub.2 H.sub.5 I                                                                          7-hydroxy-1-(2-propynyl)-                                                      β,β,9-triethyl//propionic acid        384   132          CH.sub.3 I  1-cyclobutyl-3,9-dimethyl-8-                                                   nitro-α-propyl//propionic acid            385   137          CH.sub.2 =C(CH.sub.3)CH.sub.2 Cl                                                           4,4-diethyl-1,9-dimethallyl-                                                   α,α,β,3-tetramethyl//propi                                    onic                                                                           acid                                            386   142          CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-8-chloro-β,3,3,4,4-                                               pentamethyl-1-(2-thienyl)//                                                    propionic acid                                  387   143          CH.sub.2 =CHCl                                                                             1-methyl-6-nitro-α,α,β,.be                                    ta.,3-penta-                                                                   ethyl-9-vinyl//propionic acid                   388   146          C.sub.2 H.sub.5 Cl                                                                         1-cyclopropyl-6-ethoxy-α,β,9-                                       triethyl//propionic acid                        389   150          CH.sub.3 I  1,9-dimethyl//butyric acid                      390   150          CH.sub.2 =CHCH.sub.2 Cl                                                                    9-allyl-1-methyl//butyric acid                  391   151          C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl-γ,3-dimethyl//                                               butyric acid                                    392   153          CH.sub.2 =CHBr                                                                             3,3-dimethyl-1,9-divinyl-β,γ,.ga                                    mma.,-                                                                         4-tetrapropyl//butyric acid                     393   155          CH.sub.2 =CHBr                                                                             7-chloro-1,9-divinyl-α,β,β,                                    γ,γ,-                                                              4,4-heptaethyl//butyric acid                    394   161          C.sub.2 H.sub.5 I                                                                          8,9-diethyl-α-methyl-1-phenyl//                                          butyric acid                                    395   165          CH.sub.3 I  1-benzyl-α,β-diethyl-5-propyl-                                      3,3,9-trimethyl//butyric acid                   396   168          C.sub. 2 H.sub.5 Br                                                                        7-chloro-α,α,3,4,4,9-hexaethyl-                                    1-(2-thienyl)//butyric acid                     __________________________________________________________________________

EXAMPLE 397

By following the procedure of Example 304 but using as the starting material an equivalent amount of the ester compounds of formula I in which R⁷ is hydrogen and Z is lower alkoxy, obtained prior to hydrolysis in Example 1 and 3 to 168, inclusive, instead of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b] indole-1-acetic acid, and using an equivalent amount of an appropriate lower alkyl or lower alkenyl halide, then the corresponding N-alkylated ester compounds of formula I in which R⁷ is lower alkyl or lower alkenyl, are obtained.

For example, when following the procedure of Example 304, the replacement of 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid by an equivalent amount of its corresponding ethyl ester, described in Example 1, and then use the same alkyl halide, methyl iodide, affords 1,9-dimethyl-1,3, 4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester.

Similarly, the replacement of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid by an equivalent amount of 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester, described in Example 3, affords 1,9-dimethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester.

By following the procedure of Example 170 but using as the starting material an equivalent amount of one of the N-alkylated acid compounds of formula I, described in Examples 304 to 396, inclusive, instead of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and using an equivalent amount of an appropriate amine such as ammonia or a primary or secondary amine, described in Example 170, then the corresponding amide compound of formula I in which R⁷ is lower alkyl or lower alkenyl and Z is amino, lower alkyl amino, di(lower)alkylamino or phenylamino, is obtained. Examples of such amides are listed as products in Tables VII and VIII together with the appropriate starting material, noted by the example in which it is prepared, and the amine used for the preparation of the amide.

                                      TABLE VII                                    __________________________________________________________________________           NO. OF THE EXAMPLE    PRODUCT: [(PREFIX LISTED BELOW-                          IN WHICH STARTING     1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                         MATERIAL IS           INDOLE-1-(SUFFIX LISTED BELOW)]                    EXAMPLE                                                                              PREPARED       AMINE    PREFIX//SUFFIX                                   __________________________________________________________________________     398   304          (CH.sub.3).sub.2 NH                                                                     N,N,1,9-tetramethyl//acetamide                     399   304          CH.sub.3 NH.sub.2                                                                       N,1,9-trimethyl//acetamide, m.p.                                               136 - 138°C.                                400   304          NH.sub.3 1,9-dimethyl//acetamide, m.p.                                                  105 - 106°C.                                401   304          n--C.sub.6 H.sub.13 NH.sub.2                                                            1,9-dimethyl-N-hexyl//acetamide                    402   304          (C.sub.2 H.sub.5).sub.2 NH                                                              N,N-diethyl-1,9-dimethyl//                                                     acetamide                                          403   305          CH.sub.3 NH.sub.2                                                                       9-allyl-N,1-dimethyl//acetamide                    404   305          (CH.sub.3).sub.2 NH                                                                     9-allyl-N,N,1-trimethyl//                                                      acetamide                                          405   309          CH.sub.3 NH.sub.2                                                                       N,1,9-trimethyl//propionamide                      406   309          (C.sub.2 H.sub.5).sub.2 NH                                                              1,9-dimethyl-N,N-diethyl//                                                     propionamide                                       407   311          NH.sub.3 9-allyl-1-methyl//propionamide                     408   311          (CH.sub.3).sub.2 NH                                                                     9-allyl-N,N,1-trimethyl//                                                      propionamide                                       409   313          CH.sub.3 NH.sub.2                                                                       N,1-dimethyl-9-vinyl//                                                         carboxamide                                        410   314          (C.sub.2 H.sub.5).sub.2 NH                                                              N,N-diethyl-6-hydroxy-1-                                                       (1-propenyl)-3,3,9-trimethyl//                                                 carboxamide                                        411   316          n--C.sub.6 H.sub.3 NH.sub.2                                                             N-hexyl-9-isopropyl-1-phenyl//                                                 carboxamide                                        412   317          CH.sub.3 NH.sub.2                                                                       N,9-dimethyl-1-ethyl//acetamide                    413   319          (C.sub.2 H.sub.5).sub.2 NH                                                              9-allyl-N,N,1-triethyl//                                                       acetamide                                          414   320          (CH.sub.3).sub.2 NH                                                                     N,N-dimethyl-1-ethyl-9-vinyl//                                                 acetamide                                          415   321          CH.sub.3 NH.sub. 2                                                                      N,9-dimethyl-1-propyl//                                                        acetamide                                          416   323          (C.sub.2 H.sub.5).sub.2 NH                                                              9-allyl-N,N-diethyl-1-propyl//                                                 acetamide                                          417   331          CH.sub.3 NH.sub.2                                                                       1-cyclohexyl-9-propyl-N,α,α-                                       trimethyl//acetamide                               418   332          n--C.sub.6 H.sub.13 NH.sub.2                                                            9-allyl-N-hexyl-1-(2-thienyl)//                                                acetamide                                          419   333          (CH.sub.3).sub.2 NH                                                                     6-methoxy-N,N,1,9-tetramethyl//                                                acetamide                                          420   335          CH.sub.3 NH.sub.2                                                                       9-ethyl-1-phenyl-4,4,5-                                                        tripropyl-N,α,3-trimethyl//                                              acetamide                                          421   341          (C.sub.2 H.sub.5).sub.2 NH                                                              N,N,α,α,β,β,3-heptaethyl                                 -1-                                                                            methyl-6-nitro-9-vinyl//                                                       propionamide                                       422   342          (C.sub.2 H.sub.5).sub.2 NH                                                              1-cyclopropyl-6-methoxy-N,N,-                                                  α,β,9-pentaethyl-9-vinyl//                                          propionamide                                       423   343          CH.sub.3 NH.sub.2                                                                       N,1,9-trimethyl//butyramide                        424   344          (CH.sub.3).sub.2 NH                                                                     9-allyl-N,N,1-trimethyl//                                                      butyramide                                         425   345          NH.sub.2 1,9-diethyl-γ,3-dimethyl//                                               butyramide                                         426   349          CH.sub.3 NH.sub.2                                                                       1-benzyl-α,β-diethyl-5-propyl-                                      N,3,3,9-tetramethyl//                                                          butyramide                                         __________________________________________________________________________

                                      TABLE VIII                                   __________________________________________________________________________           NO. OF THE EXAMPLE    PRODUCT: [(PREFIX LISTED BELOW-1,3,-                     IN WHICH STARTING     4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                         MATERIAL IS           INDOLE-1-(SUFFIX LISTED BELOW)]                    EXAMPLE                                                                              PREPARED     AMINE      PREFIX//SUFFIX                                   __________________________________________________________________________     427   352          (CH.sub.3).sub.2 NH                                                                     N,N,1,9-tetramethyl//acetamide                     428   352          CH.sub.3 NH.sub.2                                                                       N,1,9-trimethyl//acetamide                         429   352          NH.sub.3 1,9-dimethyl//acetamide                            430   352          n--C.sub.6 H.sub.13 NH.sub.2                                                            1,9-dimethyl-N-hexyl//acetamide                    431   352          (C.sub.2 H.sub.5).sub.2 NH                                                              N,N-diethyl-1,9-dimethyl//                                                     acetamide                                          432   351          CH.sub.3 NH.sub.2                                                                       9-allyl-N,1-dimethyl//acetamide                    433   351          (CH.sub.3).sub.2 NH                                                                     9-allyl-N,N,1-trimethyl//                                                      acetamide                                          434   355          CH.sub.3 NH.sub.2                                                                       N,1,9-trimethyl//propionamide                      435   355          (C.sub.2 H.sub.5).sub.2 NH                                                              1,9-dimethyl-N,N-diethyl//                                                     propionamide                                       436   357          NH.sub.3 9-allyl-1-methyl//propionamide                     437   357          (CH.sub.3).sub.2 NH                                                                     9-allyl-N,N,1-trimethyl//                                                      propionamide                                       438   359          CH.sub.3 NH.sub.2                                                                       N,1-dimethyl-9-vinyl//                                                         carboxamide                                        439   360          (C.sub.2 H.sub.5).sub.2 NH                                                              N,N-diethyl-6-hydroxy-1-                                                       (1-propenyl)-3,3,9-trimethyl//                                                 carboxamide                                        440   362          n--C.sub.6 H.sub.3 NH.sub.2                                                             N-hexyl-9-isopropyl-1-phenyl//                                                 carboxamide                                        441   363          CH.sub.3 NH.sub.2                                                                       N,9-dimethyl-1-ethyl//                                                         acetamide                                          442   365          (C.sub.2 H.sub.5).sub.2 NH                                                              9-allyl-N,N,1-triethyl//                                                       acetamide                                          443   366          (CH.sub.3).sub.2 NH                                                                     N,N-dimethyl-1-ethyl-9-vinyl//                                                 acetamide                                          444   367          CH.sub.3 NH.sub.2                                                                       N,9-dimethyl-1-propyl//acetamide                   445   369          (C.sub.2 H.sub.5).sub.2 NH                                                              9-allyl-N,N-diethyl-1-propyl//                                                 acetamide                                          446   377          CH.sub.3 NH.sub.2                                                                       1-cyclohexyl-9-propyl-N,α,α-                                       trimethyl//acetamide                               447   378          n--C.sub.6 H.sub.13 NH.sub.2                                                            9-allyl-N-hexyl-1-(2-thienyl)//                                                acetamide                                          448   379          (CH.sub.3).sub.2 NH                                                                     6-methoxy-N,N,1,9-tetramethyl//                                                acetamide                                          449   381          CH.sub.3 NH.sub.2                                                                       9-ethyl-1-phenyl-4,4,5-                                                        tripropyl-N,α,3-trimethyl//                                              acetamide                                          450   387          (C.sub.2 H.sub.5).sub.2 NH                                                              N,N,α,α,β,β,3-heptaethyl                                 -1-                                                                            methyl-6-nitro-9-vinyl//                                                       propionamide                                       451   388          (C.sub.2 H.sub.5).sub.2 NH                                                              1-cyclopropyl-6-ethoxy-N,N,-                                                   α,β,9-pentaethyl//propionamide          452   389          CH.sub.3 NH.sub.2                                                                       N,1,9-trimethyl//butyramide                        453   390          (CH.sub.3).sub.2 NH                                                                     9-allyl-N,N,1-trimethyl//                                                      butyramide                                         454   391          NH.sub.2 1,9-diethyl-γ,3-dimethyl//                                               butyramide                                         455   395          CH.sub.3 NH.sub.2                                                                       1-benzyl-α,β-diethyl-5-propyl-                                      N,3,3,9-tetramethyl//butyramide                    __________________________________________________________________________

EXAMPLE 456 6-HYDROXY-1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-ACETIC ACID (I; R¹ = CH₃, R², R³, R⁴, R⁵ AND R⁷ = H, R⁶ = 6-OH, X = O, Y = CH₂ CO and Z = OH)

A mixture of 6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (5.3 g., 0.015 mole), prepared as described in Example 31, in 250 ml. of anhydrous ethanol, and 1.1 g. of 10% palladium on carbon is stirred at room temperature under a hydrogen atmosphere until no more hydrogen is being taken up by the reaction mixture. The catalyst is removed by filtration through diatomaceous earth (Celite) and the filtrate concentrated. The residue is recrystallized from ethanol-benzene to afford the title compound, m.p. 170°-171°C.

The corresponding benzylamine salt is prepared by the mixing of equimolar ethereal solutions of benzylamine and the above product. The resulting solid is recrystallized from acetonitrile to afford 6-hydroxy-1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid benzylamine salt, m.p. 191°-193°C. The corresponding acetate is prepared by allowing a mixture of the title compound and a five molar excess of acetic anhydride in pyridine solution to stand for 24 hr. Dilution of the mixture with water extraction with ether and recrystallization of the extract residue from benzene-petroleum ether, affords 6-acetoxy-1-methyl-1,3,4,9-tetrahydro[3,4-b]indole-1-acetic acid, identical with the product of Example 30.

Table IX provides further examples of the compounds of this invention. The remarks relating to procedure, starting material and product applied to Table I are applicable also to Table IX. Note also that starting materials of both formulae II and IIa are utilized.

                                      TABLE IX                                     __________________________________________________________________________                                     KETOESTER OF   PRODUCT: [(PREFIX                                               FORMULA VI     LISTED BELOW)-1,5,4,9-                                          O              TETRAHYDROPYRANO-                     STARTING MATERIAL OF      ∥     [3,4-d]INDOLE-1-                EXAMPLE                                                                              FORMULA II                (R.sup.1 --C--Y--OR.sup.16)                                                                   (SUFFIX LISTED BELOW)]          R.sup.2    R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                           R.sup.6                                                                               X  R.sup.1                                                                              Y    R.sup.16                                                                           PREFIX//SUFFIX                  __________________________________________________________________________     457   H    H   CH.sub.3                                                                           H  H      0  n--C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    4-methyl-1-propyl//                                                            acetic acid, m.p.                                                              191 - 195°C.             458   H    H   H   H  5-CH.sub.3                                                                            0  n--C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    6-methyl-1-propyl//                                                            acetic acid, m.p.                                                              126 - 129°C.             459   H    H   H   H  4--i--C.sub.3 H.sub.7                                                                 0  n-- C.sub.3 H.sub.7                                                                  CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    5-isopropyl-1-propyl//                                                         acetic acid, m.p.                                                              164.5 - 165°C.           460   H    H   H   H  4--Cl  0  n--C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    5-chloro-1-propyl//                                                            acetic acid, m.p.                                                              166 - 169°C.             461   H    H   H   H  6--OCH.sub.3                                                                          0  n--C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    7-methoxy-1-propyl//                                                           acetic acid, m.p.                                                              164 - 166°C.             462   H    H   CH.sub.3                                                                           H  H      0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-ethyl-4-methyl//                                                             acetic acid, m.p.                                                              153 - 156°C.,                                                           (Isomer A), m.p.                                                               132 - 133°C (Isomer                                                     B)                              463   H    H   H   H  4--Cl  0  CH.sub.3                                                                             CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    5-chloro-1-methyl//                                                            acetic acid, m.p.                                                              183 - 184°C.             464   H    H   H   H  4--C.sub.2 H.sub.5                                                                    0  n--C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    5-ethyl-1-propyl//                                                             acetic acid, m.p.                                                              130 - 131°C.             465   H    CH.sub.3                                                                           H   H  H      0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-ethyl-3-methyl//                                                             acetic acid, m.p.                                                              147 - 148°C.,                                                           (Isomer A), m.p.                                                               145 - 146°C.,                                                           (Isomer B)                      466   H    H   H   H  4--CH.sub.3                                                                           0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-ethyl-5-methyl//                                                             acetic acid, m.p.                                                              170 - 172°C.             467   H    H   H   H  4--CH.sub.3                                                                           0  CH.sub.3                                                                             CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1,5-dimethyl//acetic                                                           acid, m.p. 150                                                                 - 151°C.                 468   H    H   H   H  4--Cl  0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    5-chloro-1-ethyl//                                                             acetic acid, m.p.                                                              154 - 157°C.             469   H    H   CH.sub.3                                                                           H  H      0  t--C.sub.4 H.sub.9                                                                   CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-t-butyl-4-methyl//                                                           acetic acid, m.p.                                                              179 - 181°C.             470   H    H   H   H  4--OCH.sub.3                                                                          0  n--C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                         C.sub. 2 H.sub.5                                                                   5-methoxy-1-propyl//                                                           acetic acid, m.p.                                                              148 - 151°C.             471   H    H   H   H  7--CH.sub.3                                                                           0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-ethyl-8-methyl//                                                             acetic acid, m.p.                                                              160 - 161°C.             472   H    H   CH.sub.3                                                                           H  7--CH.sub.3                                                                           0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    4,8-dimethyl-1-ethyl//                                                         acetic acid, m.p.                                                              129 - 131°C.             473   H    H   CH.sub.3                                                                           H  7--CH.sub.3                                                                           0  CH.sub.3                                                                             CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1,4,8-trimethyl//                                                              acetic acid, m.p.                                                              157 - 159°C.             474   H    H   H   H  7--Cl  0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    8-chloro-1-ethyl//                                                             acetic acid, m.p.                                                              168 - 171°C.             475   H    H   H   H  6--Cl  0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    7-chloro-1-ethyl//                                                             acetic acid, m.p.                                                              182 - 183°C.             476   H    H   H   H  6--Cl  0  n--C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    7-chloro-1-propyl//                                                            acetic acid, m.p.                                                              182 - 183°C.             477   H    H   H   H  7--C.sub.2 H.sub.5                                                                    0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1,8-diethyl//acetic                                                            acid, m.p. 145                                                                 - 148°C.                 478   H    H   H   H  7--OCH.sub.3                                                                          0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-ethyl-8-methoxy//                                                            acetic acid, m.p.                                                              132°C.                   479   H    H   H   H  4--CH.sub.3                                                                           0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    5,8-dimethyl-1-ethyl//                                7--CH.sub.3              acetic acid                     480   H    H   H   H  4--Cl  0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    5,8-dichloro-1-ethyl//                                7--Cl                    acetic acid                     481   H    H   H   H  6--Cl  0  n--C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    7,8-dichloro-1-propyl//                               7--Cl                    acetic acid                     482   H    H   H   H  4--Cl  0  CH.sub.3                                                                             CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    5,7-dichloro-1-methyl//                               6--Cl                    acetic acid                     483   H    H   H   H  4--CH.sub.3                                                                           0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    8-chloro-1-ethyl-                                     7--Cl                    5-methyl//acetic                                                               acid                            484   H    H   H   H  4--Cl  0  C.sub.2 H.sub.5                                                                      CH.sub. 2 CO                                                                        C.sub.2 H.sub.5                                                                    5-chloro-1-ethyl-8-                                   7--CH.sub.3              methyl//acetic acid             485   H    H   CH.sub.3                                                                           H  4--C.sub.2 H.sub.5                                                                    0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    7-bromo-1,5-diethyl-                                  6--Br                    4-methyl//acetic                                                               acid                            486   H    H   H   H  6--Cl  0  CH.sub.3                                                                             CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    7-chloro-1,8-dimethyl//                               7--CH.sub.3              acetic acid                     487   H    H   CH.sub.3                                                                           H  4--Cl  0  CH.sub.3                                                                             CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1,4-dimethyl-5,7,8-                                   6--Cl                    trichloro//acetic                                     7--Cl                    acid                            488   H    H   H   H  4--OCH.sub.3                                                                          0  n--C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-propyl-5,6,7,8-                                     5--OCH.sub.3             tetramethoxy//                                        6--OCH.sub.3             acetic acid                                           7--OCH.sub.3                                             489   H    H   H   H  4--OCH.sub.3                                                                          0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    8-chloro-1-ethyl-5-                                   7--Cl                    methoxy//acetic                                                                acid                            490   H    H   CH.sub.3                                                                           H  4--OCH.sub.3                                                                          0  CH.sub.3                                                                             CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    7,8-dichloro-1-                                       6--Cl                    methyl-5-methoxy//                                    7--Cl                    acetic acid                     491   H    H   H   H  4--OCH.sub.3                                                                          0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-ethyl-5,8-di-                                       7--OCH.sub.3             methoxy//acetic acid,                                                          m.p. 167 - 169°C.        492   CH.sub.3                                                                            H   H   H  4--F   0  n--C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    8-chloro-5-fluoro-3-                                  7--Cl                    methyl-1-propyl//                                                              acetic acid                     493   H    H   H   H  4--F   0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    7,8-dichloro-5-                                       6--Cl                    fluoro-1-ethyl//                                      7--Cl                    acetic acid                     494   C.sub.2 H.sub.5                                                                     H   CH.sub.3                                                                           H  4--CF.sub.3                                                                           0  CH.sub.3                                                                             CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    3-ethyl-5-trifluoro-                                  7--CH.sub.3              methyl-1,4,8-                                                                  trimethyl//acetic                                                              acid                            495   H    H   H   H  6--CF.sub.3                                                                           0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-ethyl-7-trifluoro-                                                           methyl//acetic acid             496   H    H   CH.sub.3                                                                           H  7--CF.sub.3                                                                           0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-ethyl-4-methyl-8-                                                            trifluoromethyl//                                                              acetic acid                     497   H    H   C.sub.2 H.sub.5                                                                    H  5--CH.sub.3                                                                           0  CH.sub.3                                                                             CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1,6-dimethyl-4-ethyl-                                 7--NO.sub.2              8-nitro//acetic acid            498   CH.sub.3                                                                            H   H   H  4--NO.sub. 2                                                                          0  n--C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    8-chloro-3-methyl-5-                                  7--Cl                    nitro-1-propyl//                                                               acetic acid                     499   H    H   H   H  5--SH  0  CH.sub.3                                                                             CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    6-mercapto-1-methyl//                                                          acetic acid                     500   H    H   CH.sub.3                                                                           H  7--SCH.sub.3                                                                          0  CH.sub.3                                                                             CH.sub.2 --                                                                         C.sub.2 H.sub.5                                                                    1,4-dimethyl-8-methyl-                                                CH.sub.2 CO                                                                             thio//propionic acid            501   H    H   H   H  6--SC.sub.2 H.sub.5                                                                   0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-ethyl-7-ethylthio//                                                          acetic acid                     502   H    H   H   H  4--NH.sub.2                                                                           0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    5-amino-1-ethyl//                                                              acetic acid                     503   H    H   H   H  6--NH.sub.2                                                                           0  C.sub.2 H.sub.5                                                                      CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    7-amino-1-ethyl//                                                              acetic acid                     504   H    H   H   H  4--SO.sub.2 NH.sub.2                                                                  0  n--C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-propyl-5-sulfamoyl//                                                         acetic acid                     505   H    H   H   H  6--SO.sub.2 NH.sub.2                                                                  0  CH.sub.3                                                                             CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-methyl-7-sulfamoyl//                                                         acetic acid                     __________________________________________________________________________ 

We claim:
 1. A compound of the formula Ia ##SPC7##in which R¹ is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, phenyl, benzyl and 2-thienyl, R², R³, R⁴ and R⁵ are the same or different and are each selected from the group consisting of hydrogen and lower alkyl, R^(6a), R^(6b), R^(6c), and R^(6d) are the same or different and selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro, halo, mercapto, lower alkylthio, trifluoromethyl, amino and sulfamoyl, R⁷ is selected from the group consisting of hydrogen, lower alkyl and lower alkenyl, X is selected from the group consisting of oxy and thio, Y is selected from the group consisting of carbonyl, ##EQU8## which each of R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ is hydrogen or lower alkyl, and Z is selected from the group consisting of hydroxy and lower alkoxy, or a pharmaceutically acceptable salt thereof.
 2. 1-Ethyl-5,8-dimethoxy-1,3,4,9-tetrahydropyrano[3,4-b]indole1-acetic acid, as claimed in claim
 1. 3. 1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester, as claimed in claim
 1. 4. 1,9-Dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 5. 1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 6. 1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester, as claimed in claim
 1. 7. 1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid, as claimed in claim
 1. 8. 1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid ethyl ester, as claimed in claim
 1. 9. 1-Methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester, as claimed in claim
 1. 10. 1-Methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 11. 1-Ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 12. 1-Propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 13. 1-Isopropyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 14. 3-Methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 15. 4-Ethyl-1-ethynyl-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 16. α, 1-Dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 17. 1-Phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 18. 1-t-Butyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 19. 1-Butyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 20. 8-Methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 21. 1-(2-Thienyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 22. 6-Bromo-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 23. 6-Methoxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 24. 6-Acetoxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 25. 6-Benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 26. 5-Methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 27. 7-Methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 28. 6-Nitro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 29. 4,4-Dimethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 30. 1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetic acid, as claimed in claim
 1. 31. 1-Ethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 32. 1-Propyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 33. 1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxylic acid, as claimed in claim
 1. 34. 1,9-Dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 35. 9-Allyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 36. 6-Hydroxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 37. 6-Hydroxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid benzylamine salt, as claimed in claim
 1. 38. 1,9-Dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid, as claimed in claim
 1. 39. 1,4,-Dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 40. 9-Ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1acetic acid, as claimed in claim
 1. 41. 1-Methyl-9-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 42. 1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-butyric acid, as claimed in claim
 1. 43. 5-Chloro-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 44. 1-t-Butyl-4-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 45. 5-Methoxy-1-propyl-1,3,4,9-tetrahydropyrano[3,4b]indole-1-acetic acid, as claimed in claim
 1. 46. 1-Ethyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 47. 4,8-Dimethyl-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 48. 1,4,8-Trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 49. 8-Chloro-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 50. 7-Chloro-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 51. 7-Chloro-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 52. 1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 53. 1-Ethyl-8-methoxy-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 54. 5,8-Dimethyl-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 55. 5,8-Dichloro-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 56. 1-Ethyl-5,8-dimethoxy-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, as claimed in claim
 1. 57. 1-Ethyl-7-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetic acid, as claimed in claim
 1. 